Packaging container for antimicrobial caps

ABSTRACT

Systems, methods, and articles for providing an antimicrobial composition to the proximal elements of a trans-dermal catheter and into the lumen of the transdermal catheter are disclosed. In an embodiment, an antimicrobial composition on surface a cap element transfers antimicrobial to the proximal end of the transdermal catheter. The system comprises an elongate member configured for insertion into a lumen of a catheter, the elongate member containing an antimicrobial.

This application is a continuation of U.S. Utility application Ser. No.14/793,492, filed Jul. 7, 2015, which is a continuation of U.S. Utilityapplication Ser. No. 14/720,378, filed May 22, 2015, now U.S. Pat. No.9,352,142, issued on May 31, 2016, which is a continuation of U.S.Utility application Ser. No. 13/915,605, filed Jun. 11, 2013, now U.S.Pat. No. 9,078,992, issued on Jul. 14, 2015, which is acontinuation-in-part of U.S. Utility application Ser. No. 13/834,755filed Mar. 15, 2013, now U.S. Pat. No. 8,622,996, issued on Jan. 7,2014; which is a continuation-in-part of Ser. No. 13/752,385, filed Jan.28, 2013, now U.S. Pat. No. 8,622,995, issued on Jan. 7, 2014; whichclaims the benefit of U.S. Provisional Application No. 61/752,959, filedJan. 15, 2013. This application is also a continuation-in-part of Ser.No. 13/547,572, filed Jul. 12, 2012, now U.S. Pat. No. 9,849,276, issuedon Dec. 26, 2017, which claims the benefit of 61/506,979, filed Jul. 12,2011, and this application also is a continuation-in-part of Ser. No.12/605,966, filed Oct. 26, 2009, now U.S. Pat. No. 9,072,868, issued onJul. 7, 2015, which claims the benefit of U.S. Provisional ApplicationNo. 61/108,716, filed on Oct. 27, 2008, the contents of which are hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to medical device systems, methods, andarticles for providing antimicrobial properties in-situ to the proximalend of catheters and drainage tubes.

BACKGROUND OF THE INVENTION

Hemodialysis catheters allow patients with renal disease to have toxinsremoved from their bloodstream. Without the use of catheters, many ofthese patients would not survive. However, long-term hemodialysiscatheters have a serious drawback in that a significant percentage ofcatheters fail due to infection, resulting in elevated mortality ratesand large annual healthcare costs associated with treatment.Furthermore, bloodstream infections are a leading cause of death in theUnited States, and many of those infections are attributable to vascularaccess devices such as hemodialysis catheters. The mortality rateassociated with such infections is considerable.

Therefore, a need exists for a manner in which infections relating tolong-term hemodialysis catheters can be reduced.

SUMMARY OF THE INVENTION

The present application is directed in part to a device for deliveringan antimicrobial composition to the proximal end of a trans-dermalcatheter, the device comprising a sealing cover configured for placementover the proximal end of a catheter; and an antimicrobial compositionpositioned on at least a portion of the interior of the sealing cover.

The present application is also directed, in various implementations, toa device for delivering an antimicrobial composition into the lumen of atrans-dermal catheter and to proximal elements of the transdermalcatheter. The device comprises a cover for installing over the end of acatheter, the cover having a protrusion configured for insertion intothe proximal end of the catheter. An antimicrobial composition ispositioned to be delivered into the catheter and/or at the end of thecatheter (such as on the threads of the catheter). At least a portion ofthe antimicrobial composition is delivered to the exterior of theproximal end of the catheter upon insertion of the protrusion on thesealing cover into the proximal end of the catheter.

The application is further directed in certain implementations to amethod of applying an antimicrobial composition to the proximal end of atrans-dermal catheter. The method includes providing a transdermalcatheter; filling at least a portion of the proximal end of thetransdermal catheter with a lock solution; clamping the transdermalcatheter near its proximal end to restrict flow of the lock solutioninto the distal end of the transdermal catheter; and inserting aprotrusion on the interior of a cover into the proximal end of thetransdermal catheter. The protrusion sufficiently displaces locksolution so as to have the lock solution flow from the proximal end ofthe catheter, thereby delivering antimicrobial composition to theexterior of the catheter.

This summary is not intended to be limiting of the invention. Theinvention is further described in the following detailed description andclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1A is a perspective view of a packaging container with two sealingcovers made in accordance with an implementation of the invention. Onesealing cover is placed in the packaging container; the other sealingcover removed from the packaging container.

FIG. 1B is a side cross section view of two sealing covers with elongatemembers inserted into a packaging container made in accordance with animplementation of the invention.

FIG. 2A is a perspective view of a sealing cover with an elongate memberand a packaging container made in accordance with an implementation ofthe invention. The sealing cover is shown with the protrusion andelongate member withdrawn from the packaging container.

FIG. 2B is a side cross section view of a sealing cover with aprotrusion and elongate member inserted into a packaging container madein accordance with an implementation of the invention.

FIG. 3A is a perspective view of a sealing cover made in accordance withan implementation of the invention.

FIG. 3B is a side cross section view of the sealing cover of FIG. 3Amade in accordance with an implementation of the invention.

FIG. 4A is a perspective view of two sealing covers made in accordancewith an implementation of the invention. The two sealing covers areshown mounted onto the proximal end of a catheter.

FIG. 4B is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing covermounted onto a catheter.

FIG. 4C is an end cross section view of a sealing cover made inaccordance with an implementation of the invention and inserted into acatheter.

FIG. 5A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, prior to the sealingcover inserted into a catheter.

FIG. 5B is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, with the sealingcover shown being mounted onto the catheter and an elongate member beinginserted into the catheter.

FIG. 5C is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, with the sealingcover shown mounted onto the catheter and an elongate member insertedinto the catheter.

FIG. 6A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, prior to the sealingcover being inserted into a catheter.

FIG. 6B is an end cross section view of the catheter of FIG. 6A.

FIG. 7A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverpartially inserted into a catheter.

FIG. 7B is an end cross section view of the sealing cover and catheterof FIG. 7A.

FIG. 8A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverpartially inserted into a catheter.

FIG. 8B is an end cross section view of the sealing cover and catheterof FIG. 8A.

FIG. 9A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coveralmost completely inserted into a catheter.

FIG. 9B is an end cross section view of the sealing cover and catheterof FIG. 9A.

FIG. 10A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverfully inserted into a catheter.

FIG. 10B is an end cross section view of the sealing cover and catheterof FIG. 10A.

FIG. 11A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverprior to being inserted into a catheter.

FIG. 11B is an end cross section view of the catheter of FIG. 11A.

FIG. 12A is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverpartially inserted into a catheter.

FIG. 12B is an end cross section view of the sealing cover and catheterof FIG. 12A.

FIG. 13 is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coveralmost completely inserted into a catheter.

FIG. 14 is a side cross section view of a sealing cover made inaccordance with an implementation of the invention, the sealing coverfully inserted into a catheter.

FIG. 15 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing relativedimensions and volumes of the sealing cover components with the sealingcover inserted into a catheter.

FIG. 16A is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, with the sealingcover inserted into a catheter.

FIG. 16B is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, with the sealingcover inserted into a catheter.

FIG. 17 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing fluid on thethreads of the proximal end of the catheter.

FIG. 18 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing at least aportion of the fluid of FIG. 17 having evaporated to leave anantimicrobial residue.

FIG. 19 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing rehydrationof a portion of the antimicrobial residue of FIG. 18.

FIG. 20 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing at least aportion of the fluid of FIG. 19 having evaporated, leaving anantimicrobial residue.

FIG. 21 is a side cross-section view of a sealing cover with a seal atthe distal end of a retaining ring made in accordance with animplementation of the invention, the sealing cover installed onto acatheter.

FIG. 22 is a side cross-section view of a sealing cover with foam alongthe threads of a retaining ring made in accordance with animplementation of the invention, and the sealing cover installed onto acatheter.

FIG. 23A is a side cross-section view of a sealing cover with aswellable tip made in accordance with an implementation of theinvention, installed onto a catheter. The tip is shown in its unswollenstate.

FIG. 23B is a side cross-section view of a sealing cover with aswellable tip made in accordance with an implementation of theinvention, installed onto a catheter. The tip is shown in its swollenstate.

FIG. 24 is a side cross-section view of a sealing cover constructedwithout an elongate member made in accordance with an implementation ofthe invention.

FIG. 25A is a perspective view of a sealing cover made in accordancewith an example implementation of the invention.

FIG. 25B is a perspective view of an insert made in accordance with anexample implementation of the invention.

FIG. 25C is a perspective view of an insert made in accordance with anexample implementation of the invention.

FIG. 25D is a perspective view of a retaining ring made in accordancewith an example implementation of the invention.

FIG. 25E is a side section view of a retaining ring made in accordancewith an example implementation of the invention.

FIG. 25F is a side cross section view of a sealing cover made inaccordance with an example implementation of the invention.

FIG. 26 is a table showing the effect of interference between aretaining ring and shoulder upon ring-insert torque.

FIG. 27 shows the concentration of microbes grown in various catheterconditions.

FIG. 28 shows a chart of survival analysis of bacteria-free cathetersunder various conditions.

FIG. 29 is a side cross section view the proximal end of a catheter,including a cover with elongate member, hub, lumen, and a clamp.

FIG. 30 is a chart showing the distribution of an antimicrobial agentwithin various segments of a catheter 48 hours after a cover made inaccordance with an example implementation of the invention was insertedinto the proximal end of the catheter.

FIG. 31 is a chart showing the quantity of antimicrobial on the internaland external surfaces of a catheter at specific points in time.

It will be noted that in some cross sectional figures the illustrationshave been simplified, such as removal of the background threads on thesealing cover so as to make the various aspects of the invention moreapparent. See, for example, FIG. 11A where those background threads areremoved, compared to FIG. 3B where the background threads are depicted.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to devices, systems, and methods forcontrolling, preventing and eliminating infectious organisms in medicaldevices, such as catheters and drainage tubes, and preventing theorganisms from entering the bloodstream. The devices, systems, andmethods deliver antimicrobial compositions into the lumen and near theentry region of catheters and drainage tubes. In particular, the presentapplication is directed to a device for delivering an antimicrobialcomposition to the proximal end of a trans-dermal catheter, the devicecomprising a sealing cover configured for placement over the proximalend of a catheter; and an antimicrobial composition positioned on thesealing cover so as to be delivered to the proximal end of the cathetersuch that the antimicrobial composition is retained in the proximal endof the catheter and/or is released onto external portions of theproximal end of the catheter.

Research and development into preventing catheter-related bloodstreaminfections (CRBSI) over the last twenty years has been focused onmethods for killing the bacteria along the inside and outside length ofthe catheter. This research has resulted in success at reducing theincidence of CRBSI in some catheter types. For instance, commerciallysuccessful antimicrobial coated catheters have resulted in a decrease inthe incidence of infection in applications that use short-term(non-tunneled) catheters.

However, these coatings wash off with use and therefore are noteffective for long-term applications. The use of long-term (tunneled,cuffed) hemodialysis catheters result in approximately 2.3 bloodstreaminfections every 1000 catheter days. Expressed another way, a patientdialyzing with a hemodialysis catheter can expect to develop abloodstream infection, on average, every 14 months.

The present invention prevents, reduces and can even eliminateinfectious organisms from the entry region of a catheter or tube, andfrom within the inner luminal surface of a catheter or other similarmedical devices by providing a means for the prolonged presence of anantimicrobial composition and/or providing a means for periodicallyscrubbing the entry region and/or lumen of the catheter or other medicaldevice to remove the infectious organisms and the biofilm in whichinfectious organisms proliferate.

The present invention includes methods and devices for killing organismsand preventing organism proliferation and biofilm formation in cathetersso that organisms aren't able to exit the catheter and enter thebloodstream of a patient. The article of the present invention prevents,or reduces the number of, organisms reaching the bloodstream byemploying any or all of the following example prevention methods: 1)physically blocking migration of organisms outside the catheter, 2)killing organisms along the threads, end face and luer connector (insideand outside of the connector) at the proximal end (outside of the body)of the catheter using an antimicrobial composition, and/or 3) killingorganisms within a confined region of the catheter using anantimicrobial composition and/or a physical barrier in the catheterlumen. A fourth mode of action, scrubbing the catheter wall (tophysically remove organisms adhered to the interior wall section uponremoving the sealing cover from the catheter) may also be used inconjunction with the other methods and devices.

The antimicrobial composition can be delivered as a coating that elutesfrom a coated elongate member, that is coated onto, or impregnated into,the elongate member (such as 250 μs of chlorhexidine acetate in a layerapproximately 2 μm thick along a 17 mm long×1.9 mm diameter elongatemember/rod). The elongate member has the added benefit of displacingfluid from within the catheter as it is inserted, transferring thesolution to the outer proximal region of the catheter connector (endface and threads).

Antimicrobial compositions from the sealing cover dissolves into thedisplaced fluid, and thereby disinfects the proximal end of theconnector. Furthermore, when the fluid dries, it deposits a coating ofchlorhexidine acetate or other appropriate antimicrobial composition onthe connector as described above. As an alternative to using theelongate member, chlorhexidine acetate or other antimicrobialcomposition may be delivered by a coating on a luer tip (such as 250 μgof chlorhexidine acetate in a layer that is approximately 20 μm thick).The luer portion is also coated with an antimicrobial composition insome embodiments (such as 50 μg of chlorhexidine acetate in a layer thatis approximately 0.4 μm thick). It is also possible to deliverantimicrobial compositions by way of the connector tip cavity (drydissolvable amount, applicable for Citrate or others requiring largeamounts of antimicrobial composition).

In an example implementation, the invention is directed to a method ofdelivering an antimicrobial composition to the proximal end of atransdermal catheter, the method comprising: a) providing a transdermalcatheter implanted within a patient, the transdermal catheter having aproximal end located outside of the patient and a distal end located atleast partially within a blood vessel of the patient, the cathetercomprising: i) a hub located at the proximal end of the catheter, ii)exterior threads on the proximal end of the hub, and iii) an interiorchannel in the hub leading from an opening at the proximal end of thecatheter to a lumen in the catheter, wherein at least a portion of theinterior channel has a tapered interior surface; b) providing anantimicrobial composition delivery device for insertion into theproximal opening of the catheter, the antimicrobial composition deliverydevice comprising: i) a tapered member configured for insertion into thecatheter hub, the tapered member configured to substantially seal theproximal end of the catheter, ii) an elongate member extending from thetapered member, the elongate member configured for insertion into thecatheter hub, iii) an antimicrobial composition positioned on theelongate member, and iv) a retaining ring comprising threads configuredto engage the exterior threads on the catheter hub; c) injecting aliquid lock solution into the transdermal catheter such that at leastthe proximal end of the transdermal catheter is substantially filledwith the lock solution; d) applying a clamp across the proximal end ofthe catheter, the clamp substantially preventing the flow of fluidsacross the clamped portion of the catheter; and e) after applying theclamp, insertion of the elongate member and tapered member of theantimicrobial delivery device into the hub located at the proximal endof the catheter. The elongate member is retained substantially withinthe hub of the transdermal catheter; wherein the tapered member of theantimicrobial delivery device sealingly engages the tapered member ofthe hub of the catheter; and wherein the antimicrobial compositionelutes into the lock solution on the proximal end of the clamp.

In certain embodiments, upon insertion of the elongate member into thecatheter hub, the antimicrobial composition does not enter the distalend of the catheter or the patient.

In certain embodiments, upon insertion of the elongate member andtapered member into the hub, at least a portion of the lock solutionflows backwards out of the hub so as to moisten the threads on theretaining ring and the threads on the hub.

In certain embodiments, upon insertion of the elongate member andtapered member of the antimicrobial delivery device into the hub: theinterior of the hub defines a first volume of lock solution, a secondvolume of lock solution, and a third volume of lock solution; the firstand third volumes of lock solution being separated by the second volumeof lock solution; and the second volume of lock solution having aconstriction such that it has a smaller cross sectional area than thefirst volume of lock solution or third volume of lock solution.

In certain embodiments, upon insertion of the elongate member andtapered member of the antimicrobial delivery device into the hub: theinterior of the catheter defines a first volume of lock solution, asecond volume of lock solution, and a third volume of lock solution, thefirst volume of lock solution having an average diameter greater thanthe average diameter of the second volume, the second volume of locksolution having an average cross sectional area less than the averagecross sectional area of first volume and third volume, and the thirdvolume of lock solution having a cross sectional area substantiallyequal to the average lumen cross sectional area of the catheter proximalto the clamp. In certain implementations the first volume of locksolution comprises lock solution located in the portion of the interiorchannel of the hub between the end of the tapered member and the end ofthe tapered interior surface of the interior channel; wherein the secondvolume of lock solution lock solution located between the end of thetapered interior surface of the interior channel and the end of theelongate member; and wherein the third volume of lock solution compriseslock solution located within the catheter between the end of theelongate member and the clamp. Optionally the second volume is less thanthe first volume, and the first volume is less than the third volume. Incertain embodiments, upon insertion of the elongate member and taperedmember into the hub, antimicrobial concentration in the first volume isinitially higher than antimicrobial concentrations in the third volume.In certain embodiments, the antimicrobial concentration in the firstvolume after 48 hours is at least ten times higher than theantimicrobial concentration in the third volume. In certain embodiments,the amount of antimicrobial in the first and second volumes after 48hours is at least three times higher than the amount of antimicrobial inthe third volume.

The antimicrobial composition forms a precipitate that possessesantimicrobial properties in some implementations; the precipitate isdeposited on the interior of the hub.

In some implementations the antimicrobial composition is coated on theelongate member. In some implementations the elongate member is entirelyproximal to the clamp. In some implementations the elongate member iscontained fully within the hub. Optionally the elongate member has across sectional area of at least 25 percent of the cross sectional areaof the narrowest point in the channel in the hub.

The elongate member may have (for example) a cross sectional area of atleast 50 percent of the cross sectional area of the narrowest point inthe channel in the hub, a cross sectional area of at least 75 percent ofthe cross sectional area of the narrowest point in the channel in thehub, or a cross sectional area less than 90 percent of the crosssectional area of the narrowest point in the channel in the hub.

In some embodiments the transdermal catheter is a hemodialysis catheterhaving two hubs, and wherein two antimicrobial devices are installed onthe two hubs.

Typically, the elongate member has a length that is greater than thelength of the tapered member. The elongate member may have a crosssectional area less than 50 percent of the average cross sectional areaof the tapered member. Optionally the elongate member has a crosssectional area less than 50 percent of the greatest cross sectional areaof the tapered member. In some embodiments the elongate member has across sectional area less than 50 percent of the smallest crosssectional area of the tapered member. The elongate member may have avolume at least 50 percent of the volume of the tapered member. Incertain embodiments the elongate member displaces a volume at least 0.03mL out of the hub. The tapered member and elongate member can be rigidlyaffixed to one another and not separable.

The present invention is also directed to a method of coating anantimicrobial composition on the proximal end of a transdermal catheter,the method comprising: a) providing a transdermal catheter implantedwithin a patient, the transdermal catheter having a proximal end locatedoutside of the patient and a distal end located at least partiallywithin a blood vessel of the patient, the catheter comprising: i) a hublocated at the proximal end of the catheter, ii) exterior threads on theproximal end of the hub; iii) an interior channel leading from anopening at the proximal end of the catheter to a lumen in the catheter,wherein at least a portion of the interior channel has a taperedinterior surface; b) providing an antimicrobial delivery device forinsertion into the proximal opening of the catheter, the devicecomprising: i) a tapered member configured for insertion into thecatheter hub, the tapered member configured to substantially seal theproximal end of the catheter, ii) an elongate member extending from thetapered member, the elongate member configured for insertion into thecatheter hub, iii) an antimicrobial composition positioned on theantimicrobial delivery device, and iv) a retaining ring comprisingthreads configured to engage the exterior threads on the catheter hub;c) injecting a liquid lock solution into the transdermal catheter suchthat at least the proximal end of the transdermal catheter issubstantially filled with the lock solution; d) applying a clamp acrossthe proximal end of the catheter, the clamp substantially preventing theflow of fluids across the clamped portion of the catheter; and e) afterapplying the clamp, insertion of the elongate member and the taperedmember of the antimicrobial delivery device into the hub located at theproximal end of the catheter; wherein upon insertion of the elongatemember, the antimicrobial composition forms an antimicrobial precipitatewithin the lock solution; and wherein the antimicrobial precipitatecoats the internal channel of the hub of the catheter. Optionally, uponthe antimicrobial precipitate coating the internal channel of the hub,the antimicrobial agent and the antimicrobial precipitate are notdelivered into the catheter lumen distal to the clamp or into thepatient. Also, the antimicrobial precipitate can be formed through achemical reaction involving a chlorhexidine ion and a chlorine ion.

The following detailed description presents a description of certainspecific embodiments to assist in understanding the claims. However, onemay practice the present invention in a multitude of differentembodiments as defined and covered by the claims.

In one aspect, the present invention includes an organism barrier at theexternal end of the catheter, also referred to herein as the proximalend of the catheter. This barrier provides a seal to keep organisms fromreaching the end face and luer portions of the connector on a catheter.This can be accomplished in a first embodiment by placing an elastomericflap or gasket (i.e., silicone, neoprene, polyurethane, etc.) that ispositioned at the end of the sealing cover's connector or,alternatively, along the inner wall of the sealing cover's locking-ring.The flap preferably makes a fluid tight seal against the outer wall ofthe catheter's connector, thereby decreasing the likelihood of microbialincursion and preventing microbial growth. In the alternative, a barriermay be formed by placing foam, either closed cell or open cell, thatpreferably contains an antimicrobial composition, along the inner wallof the sealing cover's retaining ring and/or at the most proximallocation in the sealing cover such that it will abut and seal againstthe proximal end of the catheter's connector surface (also called theend face).

An embodiment using an antimicrobial composition along the sealingcover's thread region, but not containing an organism barrier, can alsobe used to reduce the number of organisms that can enter the catheter.This reduction in the number of organisms that can enter the cathetercan be accomplished by killing organisms within the thread and end faceregion.

The sealing cover is optionally designed to transfer antimicrobialcomposition from the sealing cover to the catheter threads. This isaccomplished, for example, by displacing fluid from the catheter intothe thread region of the connector. In certain embodiments an elongatemember and luer, when entering the catheter, displace the catheter'sfluid, causing the fluid to flow out into the thread region between theconnector and the sealing cover. Antimicrobial composition dissolves inthe fluid, causing the fluid to become saturated with antimicrobialcomposition. The antimicrobial fluid produces an effective antisepticregion, killing organisms on the connector. Furthermore, as the fluiddries, antimicrobial precipitates from the fluid and is deposited ontothe catheter threads and end face. This process is repeated every time anew sealing cover is placed onto the catheter, thus replenishing theantimicrobial composition on the catheter's proximal region with eachnew sealing cover.

In a further aspect, the invention is directed to adding of anantimicrobial composition along a luer connector. This can beaccomplished, for example, by coating a male luer connector with variousantimicrobial compositions.

In an additional aspect, the invention is directed to delivery of anantimicrobial composition inside the catheter. The antimicrobial can bedelivered as a coating that elutes from a coated elongate member that iscoated on (or impregnated into) an elongate member. The elongate memberhas the added benefit of displacing fluid from within the catheter as itis inserted, thereby transferring the fluid to the outer proximal regionof the catheter connector (end face and threads). Antimicrobialcomposition from the sealing cover dissolves into the displaced fluid,thereby disinfecting the proximal end of the connector.

Furthermore, when the fluid dries, it deposits a coating ofchlorhexidine acetate or other appropriate antimicrobial compositiononto the connector as described above. As an alternative to using theelongate member, the chlorhexidine acetate or other antimicrobialcomposition may be delivered by a coating on a luer tip (such as 250 μgof chlorhexidine acetate in a layer that is approximately 20 μm thick).A minimum of 10 μg of chlorhexidine acetate on the elongate member iseffective for many organisms in some implementations. A desirableminimum of greater than 100 μg is effective for most organisms, and afurther desired minimum of 250 μg is highly effective against all of themajor target organisms.

Types of antimicrobial compositions can include, without limitation,chlorhexidine base, chlorhexidine acetate, chlorhexidine gluconate,EDTA, iodine, silver sulfadiazine, or Taurolidine; or combinationsthereof. Other antimicrobial compositions may also be used.

Typically, these methods are also used in conjunction with confinementof the antimicrobial in the catheter, such as by relying on a catheterclamp to confine the antimicrobial composition in a portion of theproximal end of the catheter (that portion of the catheter outside of apatient and in particular that portion nearest the connector on thecatheter by which fluids enter and leave the catheter). Extension tubeclamps are typically part of each hemodialysis catheter and arecurrently used to confine lock solutions that are used to help ensurecatheter patency. Using the existing clamp methodology, the risk of airembolus and lock solution entering the patient is very small andconsistent with the current state of the art for conducting hemodialysisprocedures. In other medical devices, such as catheters that do notpossess catheter clamps, a swellable sealing cover tip or otherconfinement technique, such as those described in United States patentapplication publication number US 2010/0106103, may be used.

Organism mechanical removal can also be utilized. In this regard, aportion of the elongate member can scrap the catheter wall upon removal,such as by having ribs incorporated into the elongate member. In someimplementations, after placing the elongate member into the catheter,anisotropic swelling moves ribs (or other projections) against theinterior wall of the catheter, which provides a tighter fit against thewall after swelling and further promotes mechanical removal of theorganisms when the elongate member is removed from the catheter alongwith the rest of the sealing cap. Also, in some implementations the tipof the elongate member swells (or other portions such as ribs to swell)or swelling occurs along the length of the elongate member. Generally,the elongate member's unswollen diameter is smaller than the catheterlumen when the elongate member is being inserted but swells to conformto the inner shape (or larger) of the catheter lumen to enhance themechanical removal of the organisms during removal. Variouspolyurethanes or other material may be used to produce suitableanisotropic swelling and mechanical stability; more specifically,Lubrizol 1065D is suitable for a non-swelling elongate member and TG-500is suitable for an anisotropic swelling (or isotropic swelling) tipwhich may be bonded with each other using heat bonding or other suitablemethods.

An embodiment of the invention, herein referred to as a “sealing cover”,prevents the migration of infectious organisms into the body byproviding an antimicrobial and/or physical barrier preventing movementof infectious organisms in to the catheter, as well as preventingreproduction of infectious organisms within the proximal end of thecatheter.

The sealing cover optionally contains an elongate member that can beinserted into a medical device, such as a catheter or a drainage tube.For the sake of simplicity, the term “catheter” is used for all medicaldevices in which the present invention can be inserted and used tocontrol, prevent, and eliminate infectious organisms. The sealing covermay be removed from the catheter to allow the catheter to be used in adialysis procedure or other procedure. After the procedure is complete,a new sealing cover may be used to seal and protect the catheter. Theremoval of one sealing cover and the replacement with a new sealingcover may be repeated an indefinite number of times. With each newsealing cover, the antimicrobial composition inside and outside of thecatheter is reestablished. Another aspect is that antimicrobialcomposition is transferred from the sealing cover to the catheter witheach use.

In the case of using the sealing cover with dialysis catheters, thepresent invention is generally designed to be replaced regularly aftereach dialysis session, approximately three times per week. Thisreplenishes the antimicrobial composition with each replacement,resulting in a consistent and high concentration of antimicrobialcomposition present within and upon the catheter on an ongoing basisresulting in decreased risk of infection. However, the confinementmethod, such as clamps, as used in conjunction with the invention,prevents a significant amount of antimicrobial composition from leakinginto the bloodstream on a regular basis, which also maintains a higherconcentration of antimicrobial composition in the proximal end of thecatheter, where a significant danger of microbe infiltration exists.

In addition, separation between the antimicrobial composition and bloodcan result in lower infection rate, fewer side effects, and less risk ofdeveloping resistant bacteria because a non-antibiotic antimicrobial isused. In certain embodiments, the present invention creates a physicalbarrier between the blood and the antimicrobial composition. The barriergreatly reduces the exchange of antimicrobial composition with bloodcirculating in the body, resulting in fewer side effects from theantimicrobial composition. This can result in a more consistent level ofantimicrobial composition along the length of the catheter adjacent tothe sealing cover. Additionally, the barrier reduces the amount ofantimicrobial composition entering the bloodstream, thus reducing therisk of an adverse reaction to the composition or developing organismsresistant to the antimicrobial composition.

In comparison, it is well-known that liquid locking compositions can anddo routinely migrate into the bloodstream, and the blood can migrateinto the catheter, thus reducing the effectiveness of the antimicrobialcomposition, increasing the possibility of bacteria entering thebloodstream and increasing the rate of thrombosis in the catheter. Theact of flushing the catheter lumen with a fluid composition into thelumen will result in the removal of blood from the lumen and thus reducethe risk of thrombosis. If the liquid composition is an anti-thromboticlock, such as heparinized saline or saline with 4% sodium citrate, therisk of thrombosis is further reduced. The use of a confinement means,as described in the present invention as a swellable elongate membertip, swellable elongate member, or catheter clamp, prevents the bloodfrom reentering the lumen and results in a lower risk of thrombosis inthe lumen.

A further aspect of the invention relates to protecting the sealingcovers from contamination prior to use and during handling in order tokeep the elongate member and luer sterile prior to insertion into thecatheter. A package that covers the elongate member and luer may beused. A standard package, which protects one luer and elongate member,is suitable for keeping one elongate member and luer sterile. A novelpackage is hereafter described which improves handling while maintainingsterility protection and facilitates low-cost injection molding.

The packaging container holds two sealing covers, where the two sealingcovers are held 180 degrees opposed in an axially offset manner,typically with at least a portion of the two elongate members axiallyoverlapping one another, with a physical barrier between the two sealingcovers. The packaging container functions as a shield to protect thesealing cover, and also to maintain sterility of the sealing cover aswell as to prevent loss of the antimicrobial composition located on theportions of the sealing cover that will be inserted into the catheter.

The packaging container may have threads to provide a means forremovably attaching the sealing covers to the packaging body. Thisconfiguration allows the user to hold one piece rather than two, thuseasing handling and decreasing the risk of dropping the sealing covers.The barrier between the two sealing covers ensures that, when onesealing cover is removed from the packaging container, that the othersealing cover remains sterile. The sealing covers, secured within thepackaging, may be contained in a pouch using a suitable material, suchas a metal film with a polymer laminate to facilitate heat sealing. Themetal layer is useful to minimize adverse effects of humidity. Thedevice, inside the pouch, may be sterilized using gamma radiation orother suitable sterilization method. Gamma radiation has the advantageof effectively sterilizing the product while it is contained withinmoisture-proof packaging.

Referring now to the figures, example implementations of the inventionare shown. FIG. 1A shows an exploded view of a packaging containersystem 210 that includes an arterial sealing cover 220, a venous sealingcover 320, and a packaging container 250. The packaging container system210 contains two sealing covers within the same packaging container 250.Colors of the sealing covers are typically chosen to match the standardcolors used in hemodialysis: red for the arterial sealing cover 220 andblue for the venous sealing cover 320. Typically, the arterial sealingcover 220 and venous sealing cover 320 are identical other than color.

Packaging container 250 provides for easier handling and storage of thesealing covers 220 and 320 because there are relatively few parts tohandle and hold. The packaging container system 210 is optionallyshipped and stored within a heat-sealed foil-pouch (not shown) and gammasterilized, although other packing and sterilization techniques can beused. The foil-pouch is generally opened at the clinic immediatelybefore use of the sealing covers. Sealing cover threads 141 removablyengage packaging container threads 159 to allow easy removal of thesealing covers 220, 320 from the packaging container 250. The sealingcover 220 also shows a central protrusion 131 comprising a furtherelongate member 133 extending beyond the central protrusion 131. Aflattened side 157 of the packaging container 250 creates a convenientfeature for gripping the packaging container 250 as the sealing covers220, 320 are removed. In addition, the flattened side 157 of packagingcontainer 250 disrupts the rotational symmetry of the packagingcontainer 250, thus making the packaging container system 210 resistantto rolling onto the floor or being dropped.

FIG. 1B shows a cross section of a packaging container system 210 withan arterial sealing cover 220 and a venous sealing cover 320, eachinserted into a packaging container 250, identical to the packagingcontainer system 210 but with both sealing covers 220 and 320 installedon the packaging container 250. The packaging container 250 is designedto keep the sealing covers 220, 320 axially offset as shown by thearterial sealing cover axis 154 and the 20 venous sealing cover axis254. The offset axis is advantageous over a coaxial design because itdecreases the length of the system 210, allowing it to fit into ashorter pouch and making it easier to handle. The container includes abody 251 with a first end 255, the first end 255 having a first opening253 leading to a first volume 257 within the body 251; and a second end265, the second end 265 having a second opening 263 leading to a secondvolume 267 within the body 251; the first and second openings 253, 263configured to each hold one of the two antimicrobial covers. Inaddition, the sealing covers 220, 320 are 180 degrees opposed from eachother, thus making the retaining rings 240, 340 physically separatedfrom one another. This makes the retaining rings 240, 340 easier tograsp because the arterial retaining ring 240 does not physically 25block finger access to the venous retaining ring 340, and vice versa.

The packaging container 250 provides protection to the sealing covers220, 320 and further promotes sterility prior to use because each of thesealing covers 220, 320 are separated by a wall 256. In an exampleembodiment, the most proximal portion 231 of a central protrusion 131 onsealing cover 220 contacts the receiving edge 158 of the packagingcontainer 250. The central protrusion 131 functions as a protrusion forsubsequently engaging the proximal end of a catheter to seal theproximal end of the catheter. In the embodiment shown in FIG. 1B, thecentral protrusion 131 includes a further elongate member 133 extendingbeyond the central protrusion 131. In example embodiments most of thecentral protrusion 131 does not contact the wall 256, and therebyminimizes the risk of removing antimicrobial coating on the centralprotrusion 131. Typically, the elongate member 133 also does not contactthe wall 256 so as to minimize the risk of removing the antimicrobialcoating in the event that the elongate member 133 is coated with anantimicrobial composition.

FIG. 2A shows a perspective view of a mono packaging container system110 with a sealing cover 120, and a packaging container 150. Thepackaging container 150 allows for retention of one sealing cover withinthe housing of the packaging container 150. The mono packaging containersystem 110 can be packaged within a heat-sealed foil-pouch (not shown)and gamma sterilized. The foil-pouch is typically opened at the clinicimmediately before use of the sealing cover 120. The sealing coverthreads 141 removably engage the packaging container threads 159 toallow easy removal of the sealing cover 120 from the mono packagingcontainer 150.

FIG. 2B shows a cross sectional view of the mono packaging containersystem 110 of FIG. 2A with a sealing cover 120 inserted into a monopackaging container 150. The sealing cover 120 is inserted into the monopackaging container 150. The mono packaging container 150 providesprotection to the sealing cover 120 and further ensures that sterilityis maintained prior to use. This is accomplished by enclosing thesealing cover 120 by a wall 156. In an example embodiment the mostproximal portion 231 of the central protrusion 131 contacts thereceiving edge 158 of the mono packaging container 150. In this exampleembodiment the rest of the central protrotrusion 131 does not contactthe wall 156, and thereby minimizes the risk of removing antimicrobialcoating on the central protrusion 131. The elongate member 133 alsopreferably does not contact the wall 156 in order to minimize the riskof removing the antimicrobial coating.

FIG. 3A shows a sealing cover 120 made in accordance with an exampleimplementation of the invention. The sealing cover 120 can be, incertain example implementations, injected molded as a single unit out ofa thermoplastic polymer resin to allow high volume production at lowmanufacturing costs. The sealing cover 120 includes a central protrusion131 formed as a male luer connector configured to engage a female luerconnection at the proximal end of a transdermal catheter. The centralprotrusion 131 formed as a male luer connector in the depictedembodiment includes a further elongate member 133. The elongate member133 optionally functions to deliver antimicrobial compositions into theinterior of the proximal end of transdermal catheters.

In addition, the elongate member 133 provides a volume that aids indisplacing fluids within the proximal end of transdermal catheters,including displacing fluids such that they exit from the proximal end ofthe transdermal catheter so as to deliver antimicrobial compositions tothe proximal end of the transdermal catheter (such as to the end of thecatheter hub and the threads on the catheter hub. This displacement offluid, combined with the delivery of an antimicrobial composition intothe catheter, results in a flow of antimicrobial composition containingfluid out through the proximal end of the transdermal catheter. In thealternative, or in addition, the displacement of fluids from theproximal end of the transdermal catheter can result in moisteningantimicrobial compositions that are coated on the central protrusion 131formed as a male luer connector, as well as on the sealing cover threads141 and on the interior of the sealing cover 120. This moistening of theantimicrobial composition can bring the antimicrobial composition intosolution, thereby killing microbes near the proximal end of thecatheter—both within the catheter and, in specific embodiments, on theoutside of the catheter.

In this manner, antimicrobial compositions are delivered to locationsalong the exit path for the displaced fluid: along the luer connection,at the end of the transdermal catheter, and at threads on both thesealing cover 120 and on the external threads on the proximal end of thecatheter. Thus, multiple processes can combine to reduce the populationof microbes at the proximal end of the catheter, thereby preventing orlimiting their migration into the interior of the catheter, from wherethey could otherwise subsequently migrate into a patient's bloodstream.

The elongate member 133 is generally formed of a polymeric material thatallows it to be bent without breaking. Polymers with a minimumelongation at break of 100% are preferred. In addition, the polymer willtypically allow a solvent (which is used in the antimicrobialcomposition coating process) to wet the surface evenly until the solventevaporates, and an antimicrobial composition will typically adhere wellto the surface of the elongate member 133 such that the coating does notflake or fall off during handling. Various polymer materials may be usedthat meet these requirements, such as polyester, nylon, polyetherimide,polypropylene, polyvinyl chloride or other similar materials.Alternatively, the elongate member 133 may be manufactured using adissolvable material that is impregnated with an antimicrobialcomposition, such that the antimicrobial is released into the solutionwhen the elongate member 133 dissolves.

Portions of the sealing cover 120 are typically coated and/orimpregnated with an antimicrobial composition. In one embodiment, theantimicrobial composition is applied as a coating, with differentamounts optionally applied to the elongate member 133, the centralprotrusion 131, and the sealing cover threads 141. The antimicrobialcomposition can also be incorporated within the bulk polymer material,but coating the surface is preferred because surface coatings cangenerally be released into solution more rapidly than bulk agents;additionally, surface coatings tend to require less overallantimicrobial composition than bulk agents because the antimicrobialcomposition on the surface is more readily dissolved. In someimplementations a combination of surface coatings and incorporation intobulk polymer materials is used.

Suitable methods of coating the sealing cover 120 are spraying anddipping, with spray coating being desirable because the amount ofantimicrobial composition applied to each region (elongate member 133,central protrusion 131, and sealing cover threads 141) can more easilybe adjusted without affecting the amount located on other regions.

Silicone, fluropolymers or other lubricious coatings may also be appliedto the central protrusion 131 to reduce the amount of torque required toremove the sealing cover from the catheter hub.

FIG. 3B shows a cross section of a sealing cover 120 made in accordancewith an embodiment of the invention. The length and diameter of theelongate member 133 is sized to fit into the proximal end of a catheter,in particular into the hub of a catheter. In the embodiment describedherein, the catheter is a hemodialysis catheter. The central protrusion131 and the sealing cover threads 141 can be manufactured in accordancewith the International Organization for Standardization standard ISO594-2:1998(E) to be compatible with all hemodialysis catheters which aremade according to the standard. In certain embodiments the cover threads141 are coated with an antimicrobial composition.

FIG. 4A depicts an example hemodialysis catheter 170 for use inconjunction with an embodiment of invention, and is shown with anarterial sealing cover 220 in the arterial hub 272, and a venous sealingcover 320 in the venous hub 372. When used with a hemodialysis patient,the two-lumen tube 187 is partially tunneled below the patient's skin,from the upper chest to the jugular vein. The two-lumen tube 187 entersthe jugular vein and continues until the catheter tip 189 is in theregion of the right atrium of the heart. The arterial lumen 188 runsinside the catheter 170 from the arterial hub 272 until exiting at thecatheter tip 189. The venous lumen 288 similarly runs inside thecatheter 170 until it exits near the catheter tip 189. If bacteria orfungus are in either or both lumens 188, 288, these infection-causingorganisms may enter the bloodstream and result in a systemic bloodstreaminfection, and therefore prevention of the entry and growth ofmicroorganisms into the catheter 170 is important.

The catheter contains a junction 186 where the extension tubes 180transition from two tubes with two lumens into one tube with two lumens;the two lumens 188, 288 run from hubs 272, 372 to catheter tip 189without fluidly connecting with the other lumen. The arterial hub 272 isattached to the proximal end of one extension tube 180, and the venoushub 372 is attached to the proximal end of the other extension tube 180.In the depicted embodiment, a clamp 184 is positioned on each of theextension tubes 180, allowing the flow in the lumen to be blocked oropened. In practice, the clamps 184 are closed except during a dialysissession or other transferring of fluids within the catheter 170. Theclamps 184 are typically repositioned each time they are opened in orderto minimize the risk of damaging the extension tube 180 through multipleclamping in the same location. The clamps 184 are generally closed priorto insertion of either sealing cover 220, 320. In this manner, thesealing covers 220, 320 do not have any portion that project deeply intothe catheter. Instead, in an example embodiment, the design is such thatthe sealing covers primarily project into the hubs 272, 372 withelongate member 133 (see FIG. 3B, for example), being contained in theproximal end of the catheter, often just in the hub, such as so they maybe inserted while the clamp is closed. This design also provides for theforcing of fluid with the proximal end of the catheter out the end ofthe catheter upon insertion of the elongate member into the catheterhub. Thus, the design as shown actually promotes the flow of fluid outthe proximal end of the hub, rather than deeper into the catheter.

In reference to FIG. 4B, a cross section of the proximal end of acatheter and sealing cap are shown. Clamp 184 is shown located in closeproximity to the hub 172. The clamp 184, when closed, creates a pinchpoint 185 which blocks the fluid flow in the lumen, creating a proximalregion in the catheter lumen on the proximal side of the clamp, and adistal region in the catheter lumen distal from the clamp. Preferablythe elongate member 133 is short enough to ensure that the clamp 184does not clamp onto the elongate member 133. Thus, the elongate membertypically does not extend beyond the hub 172. The elongate member 133should preferably be stiff enough to allow for insertion into the hub172 without requiring sheaths, tubes or other insertion aids.

In addition, the elongate member 133 must possess a small enoughdiameter to ensure that it can physically fit within the hub lumen 179.In embodiments where the elongate member 133 is long enough to enterextension tube 180 extending from the hub 172, the diameter of theextension tube 180 must also accommodate the elongate member.

The surface area of the elongate member 133 should be large enough toallow for the desired amount of antimicrobial composition to be coatedon the surface using spraying or dipping operations (or otherapplication methods, including incorporation directly into the elongatemember). The surface area is generally sized to produce an acceptabledissolution rate such that the antimicrobial composition enters the locksolution at an acceptable rate and dosage. It is desirable for theantimicrobial composition to reach an effective level within an hour ofthe sealing cover 120 being inserted into the catheter 170.

If the elongate member extends into the pinch point 185 of the clamp184, it can potentially cause damage or leaking of the lock solutionpresent within the catheter. Therefore, the length of the elongatemember 133 should be sufficiently short to ensure that it does not reachthe pinch point 185 of the clamp 184. Suitable diameters for theelongate member 133 include 1.0 mm to 2.0 mm; and 1.7 mm to 1.9 mm. Asuitable length includes less than 20 mm for the elongate member 133,alternatively less than 10 mm, less than 30 mm, or less than 40 mm. Aparticularly desirable length is 17 mm to 19 mm, but can vary for usewith various catheters. Typically, the elongate member 133 is longerthan central protrusion 131. For example, the elongate member can befrom 1 to 10 times the length of the central protrusion 131. In someimplementations the elongate member can be from 1 to 5 times the lengthof the central protrusion 131, in certain embodiments the elongatemember is from 1 to 2.5 times the length of the central protrusion 131.It is also possible to have the elongate member 133 be shorter than thecentral protrusion 131. Generally, the elongate member 133 issignificantly thinner than the central protrusion 131, such as less thanhalf the diameter of the widest diameter of the central protrusion 131.

In reference now to FIG. 4C, an embodiment is depicted showing the endsection view A-A as indicated in FIG. 4B. The sealing cover 120 is shownfully inserted into the catheter hub 172. When fully inserted, thecentral protrusion 131, formed as a male luer, contacts the female luer175 to create a fluid tight seal. Threads 141 of the sealing cover 120engage the catheter threads 178 to retain the sealing cover 120 on thehub 172. However, even after the sealing cover 120 is fully insertedinto the hub 172, a void 194 is often present between the retaining ring140 on the sealing cover 120 and the hub 172. This void 194 can be apathway for pathogenic organisms to travel along, thus allowingcontamination of the hub surfaces with pathogenic organisms in theregion between the retaining ring 140 and the hub 172. In order toreduce the incidence of catheter-related bloodstream infections, it isdesirable to reduce or eliminate the number of pathogenic organisms inthis region.

Referring now to FIG. 5A to 5C, various stages of installation ofsealing cover 120 are shown, wherein the insertion of the sealing cover(with an elongate member) results in the flow of an anti-microbialcontaining liquid out the end of the catheter hub to kill microorganismsthat would otherwise potentially intrude into the hub and then thecatheter lumen. In FIG. 5A, the sealing cover 120 is shown immediatelyprior to being inserted into the hub 172 of a catheter 170. Within thehub lumen 179 is a liquid lock solution 190, the most proximal portionof which forms a meniscus 192. The lock solution for hemodialysiscatheters is most often heparinized saline (100 IU/ml to 5000 IU/ml ofheparin), sodium citrate solution (typically 4% sodium citrate), orsaline. Patient care technicians and nurses are trained to keep themeniscus 192 at the proximal end 174 of the hub 172. However, it is notunusual for the meniscus to fall several millimeters within the hublumen 179. The antimicrobial composition must produce the desired effectin any of the standard lock solutions. In practice, the clamp 184remains closed (producing a pinch point 185) unless fluids are beingtransferred through the catheter 170.

In reference to FIG. 5B, the elongate member 133 is shown partiallyinserted into the hub lumen 179. The elongate member 133 displaces locksolution 190, which results in the meniscus 192 being pushed out of thelumen 179 and onto the end face 176 of the hub 170. Eventually, as thesealing cover 120 continues to be inserted, the meniscus 192 (and locksolution 190) will travel over the catheter threads 178, bringingantimicrobial to those threads.

Next, referring to FIG. 5C, the sealing cover 120 is shown fullyinserted into the catheter 170. In this embodiment, the meniscus 192travels beyond the void 194, completely filling the void 194 with locksolution. The lock solution causes the antimicrobial composition todissolve, resulting in a transfer of antimicrobial composition from oneor more of the coated parts (the elongate member 133, the centralprotrusion (male luer) 131, and sealing cover threads 141) into thesolution. In addition, insertion of the elongate member into the locksolution further causes a transfer of antimicrobial composition to thepreviously uncoated parts such as the wall defining the inner hub lumen179 and extension lumen 182, the female luer 175, the end face 176, andthe catheter threads 178. Within several hours the solution within thevoid 194 may dry, but a coating of an antimicrobial composition remains.

In this manner a coating of an antimicrobial composition becomestransferred to the catheter threads 178 and the end face 176, resultingin an enhanced ability to kill any organisms on the catheter threads 178and the end face 176, even if the organisms contaminate the surfacesafter the solution dries. In practice, the void is often timesinfiltrated with sweat that contains organisms. In this scenario thedried antimicrobial composition becomes hydrated by the sweat, killingorganisms that may be present in the sweat. Furthermore, the catheterthreads 178 and the end face 176 become replenished with additionalantimicrobial composition every time a new sealing cover 120 isinserted. In current practice, a new sealing cover is used after everydialysis session. The ability of the sealing cover 120 to replenish theantimicrobial composition on a catheter 170, into a targeted locationwith a high risk of serving as a microorganism source, overcomes asignificant shortcoming of antimicrobial coated catheters in which theantimicrobial composition wears off with use or is only applied to theinterior of the catheter. A desirable amount of antimicrobialcomposition on the catheter threads 178 and sealing cover threads 141 is20 μg to 2 mg, alternatively 200 μg to 1.5 mg, and desirably 500 μg to1.2 mg of chlorhexidine acetate. However, it will be understood thatdifferent levels can also be achieved with success.

Typically, the central protrusion 131 makes contact with the female luer175 to create a fluid tight seal. These parts are typically manufacturedin accordance with the International Organization for Standardizationstandard ISO 594-2:1998(E) in order to ensure proper sealing andintermateability. However, the junction between the male luer formingthe central protrusion 131 and the female luer 175 is not fluid tightalong the entire length of the interface. Some manufacturers of medicaldevice hubs intentionally manufacture their female luers such that themale luer contacts the female luer near the male luer end face. This isdone in order to reduce the risk of the splitting the hub. However, theunintended consequence is that proximal end of the luer interface allowsfor the potential infiltration of organisms.

Under prior practice, once the organisms are present, they may be pushedfurther into hub lumen 179 by current sealing covers (or other devices)the next time a sealing cover (or other device) is inserted. Once theorganisms are within the hub lumen (distal to the male luer) they canmultiply, resulting in planktonic and sessile organisms, and eventuallya biofilm. This problem can be countered by placing an antimicrobialcomposition along the central protrusion 131. The antimicrobialcomposition kills organisms that may be or become present along thefemale luer 175 before the organisms have a chance to be pushed into thehub lumen 179 or further multiply. Even with these protective measures,there is still a possibility that some organisms can make it beyond thefemale luer 175. To overcome that potential shortcoming, antimicrobialcomposition may also be present on the elongate member 133, whichdissolves or elutes into the lock solution 190, to kill organisms in thehub lumen.

The minimum amount of antimicrobial composition on the elongate member133 is the amount required to obtain an acceptable reduction (alsoreferred to as kill) of infection causing organisms. The volume ofsolution that the antimicrobial composition dissolves into is importantto understand because the more solution that is present, the more dilutethe antimicrobial composition can become. The confined volume of locksolution 190 within the lumen is defined by the location of the meniscus192, the geometry of the hub lumen 179, the geometry of the extensionlumen 182, and the location of the pinch point 185. Since each of theseitems may vary, there is a considerable range of confined fluid volumesthat is possible. After accounting for the design variations of existinghemodialysis catheters, it is evident that an example embodiment needsto produce a therapeutic concentration of antimicrobial compositionwithin a 0.7 ml volume. In one embodiment, the amount of chlorhexidineacetate on the elongate member 133 is 10 μg to 5 mg. In an alternativeembodiment, the amount of chlorhexidine acetate is 100 μg to 2 gm. Inyet another embodiment, the elongate member contains 250 μg to 550 μg ofchlorhexidine acetate.

The desired maximum amount of antimicrobial composition that is placedon each of the sealing cover's surfaces was developed by first reviewinghow much antimicrobial is safe for the patient and then comparing thatto how much antimicrobial composition the patient can potentially beexposed to by each of the sealing cover's 120 surfaces that containantimicrobial composition (elongate member 133, central protrusion 131,and sealing cover threads 141). The amount of antimicrobial that is safefor the patient was determined by reviewing published information onlevels (especially bloodstream levels) that are generally regarded assafe for patients.

Testing was conducted in order to derive how much antimicrobialcomposition the patient can potentially be exposed to from sealing cover120. The testing was designed to determine the transfer efficiency ofantimicrobial composition from each applicable component (elongatemember 133, central protrusion 131, and sealing cover threads 141) tothe bloodstream. In order to determine the potential bloodstream level,consideration was given for potential patient exposure that could occurunder a variety of conditions, including unusual use or misuse (such asinjecting the lock solution into the patient's bloodstream instead ofaspirating the solution). The potential patient exposure was determinedfor each component individually and for the entire sealing cover 120.

These embodiments can produce broad spectrum kill of the targetorganisms, yet result in a low enough dose of chlorhexidine acetatethat, even if all of the lock solution containing chlorhexidine acetateis injected directly into the bloodstream, it will result in abloodstream level that remains at safe levels. Thus, the presentinvention is characterized by relatively high concentrations ofantimicrobial compositions in the relatively low fluid volumes, but thequantity of actual antimicrobial used is relatively small. Also, theantimicrobial is generally able to be kept from meaningfully being addedto the patient's bloodstream because the antimicrobial is generallycontained to the proximal (outside of the body) portion of the catheter,and because relatively small quantities of antimicrobial materials areeven used.

Furthermore, it will be understood that in typical embodiments a certainpercent of the antimicrobial doesn't even get delivered and retainedwithin the catheter, but rather is delivered to the exterior proximalend of the catheter, such as the end of the hub and threads on theexterior of the hub. This positioning of the antimicrobial in theselocations results in potentially higher exclusion of microbialorganisms, while also avoiding adding antimicrobial compositions to thepatient's bloodstream. In some example implementations up to 50 percentof the antimicrobial is delivered to the outside surfaces of theproximal end of the catheter; in other implementations up to 25 percentof the antimicrobial composition is delivered to the outside surfaces ofthe proximal end of the catheter; and in yet other implementations up to10 percent of the antimicrobial composition is delivered to the outsidesurfaces of the proximal end of the catheter.

In an embodiment of the invention the antimicrobial composition ischosen for its ability to form fine antimicrobial particles within thelock solution through a chemical reaction known as precipitation. Thepreferred antimicrobial composition forms precipitate within the mostcommon lock solutions such as heparin and saline. The preferredantimicrobial composition creates a precipitate that settles on thecatheter wall at the proximal end of the catheter, resulting in aneffective antimicrobial coated catheter. A preferred antimicrobialcomposition is chlorhexidine acetate. Other antimicrobial compositionsmay also be chosen for their ability to precipitate, such as the otherchlorhexidine salts.

In such embodiments, a substantial amount of chlorhexidine precipitateremains on the wall of the catheter, even after flushing the locksolution from the catheter and further rinsing with a saline flush, thusit has been demonstrated that the invention imparts antimicrobialproperties to the catheter even after the antimicrobial delivery deviceis removed. In addition, in certain embodiments the amount ofantimicrobial composition on the catheter wall increases with repeateduse of this invention. Laboratory experiments demonstrated that theamount of antimicrobial composition on one or more of the followingcatheter surfaces: the extension lumen 182, hub lumen 179, female luer175, proximal end 174, and the catheter threads 178, increased withmultiple uses of certain embodiments of the sealing cover 141. Theinvention may be used to create an antimicrobial coating on the catheterhub threads, the catheter end face, the catheter luer taper, theinterior channel of the hub, or combinations thereof.

In reference now to FIG. 6A, a side cross section view of a sealingcover 120 made in accordance with an implementation of the invention isshown, prior to the sealing cover 120 being inserted into a catheter.The sealing cover 120 includes sealing cover threads 141 and elongatemember 133 configured to be inserted into the proximal end of thecatheter. The elongate member 133 displaces lock solution 190, whichresults in the meniscus 192 being pushed out of the catheter onto theend face 176 of the catheter 170. Eventually, as the sealing cover 120continues to be installed, the meniscus 192 (and lock solution) willtravel over the sealing cover threads 141. This transfer of fluid ontothe threads 141 can assist in delivering antimicrobial compositions tothe threads of the catheter hub, either by transferring antimicrobialfrom the threads 141 to the catheter hub, or by carrying antimicrobialfrom the elongate member 133 (and/or the central protrusion) to theexterior of the catheter hub, including the spaces between threads onthe catheter hub and threads on the sealing cover 120. FIG. 6B shows anend cross section view of the hub 172 of FIG. 6A taken along lines A-A′of FIG. 6A.

In reference now to FIG. 7A, a side cross section view of a sealingcover made in accordance with an implementation of the invention isshown, the sealing cover 120 shown partially inserted into a catheter.As the sealing cover 120 is inserted into the catheter the elongatemember 133 displaces lock solution 190, such as to move the meniscus 192proximally as the lock solution 190 is displaced out of the hub 172. Thesealing cover 120 can be inserted after a clamp is placed on thecatheter to clamp the catheter shut; this prevents the displaced locksolution from flowing distally from the catheter and results in thedisplaced lock solution and meniscus 192 moving proximally. FIG. 7Bshows an end cross section view of the sealing cover partially insertedinto a catheter of FIG. 7A taken along lines A-A′ of FIG. 7A, with theelongate member 133 partially inserted into the female luer 175.

Referring to FIG. 8A, a side cross sectional view of a sealing cover 120made in accordance with an implementation of the invention, the sealingcover 120 is partially inserted into a catheter. As the sealing cover120 progresses further into the catheter more lock solution 190 isforced out, and the meniscus 192 can increase in size from theadditionally displaced lock solution. The sealing cover threads 141contacts the meniscus 192 of the lock solution 190 in the depictedembodiment, thereby either receiving antimicrobial composition from thelock solution, and/or adding further antimicrobial composition to thelock solution.

Next, FIG. 8B shows a cross sectional view of the catheter and hub takenalong lines A-A′ of FIG. 8A. As the sealing cover 120 is inserted intothe catheter a gap 196 can be defined, such as between the centralprotrusion 131 (formed as a male luer) and the female luer 175. The gap196 can be at least partially occupied by lock solution 190, such as toallow lock solution 190 to pass from the catheter to the sealing coverthreads 141.

FIG. 9A is a side cross section view of a sealing cover 120 made inaccordance with an implementation of the invention, the sealing cover120 almost completely inserted into a catheter. As the sealing cover 120progresses into the catheter an air bubble 193 can form in the sealingcover, yet the lock solution 190 and minuscus 192 continue to progressto further cover the sealing cover threads 141. Further, FIG. 9B is aclose-up of the side cross sectional view taken along lines A-A′ of FIG.9A. A gap 196 can be at least partially be defined between the centralprotrusion 131 and the female luer 175, such as to permit lock solution291 to pass from the catheter to the sealing cover 120.

In reference to FIG. 10A, a side cross section view of a sealing cover120 made in accordance with an implementation of the invention, thesealing cover 120 fully inserted into a catheter hub. A highconcentration antimicrobial composition within lock solution 190 can belocated in hub 172. The lock solution can be trapped in the gap 196. Thelock solution can no longer pass through the gap 196 and the locksolution is disposed on the sealing cover threads 141. In animplementation of the invention, the elongate member 131 is entirelyproximal to the clamp; therefore, the sealing cover 120 can be removedfrom the catheter while the catheter is still clamped shut. Referring toFIG. 10B, an end cross section view of the sealing cover 120 of FIG. 10Ataken along lines A-A′ of FIG. 10A is shown. The gap 196 can besufficiently narrow to prevent further flow of lock solution 190 fromthe catheter to the sealing cover 120.

In reference to FIG. 11A, a side cross section view of a sealing cover120 made in accordance with an implementation of the invention is shown.The sealing cover 120 does not, in this embodiment, include an elongatemember. A meniscus 192 can form where the male luer defining centralprotrusion 131 enters the catheter. Further, FIG. 11B shows an end crosssection view of the catheter hub of FIG. 11A. The female luer 175 is atleast partially filled with lock solution 190. The lock solution canform a meniscus 192 where the central protrusion 131 enters the femaleluer 175, as shown in FIG. 11A.

In reference now to FIG. 12A, a side cross section view of a sealingcover 120 made in accordance with the implementation of FIG. 11A isshown, the sealing cover 120 partially inserted into a catheter. As thecentral protrusion 131 (formed as a male luer) is inserted further intothe female luer 175, more lock solution 190 is displaced from thecatheter and the meniscus 192 moves proximally as the volume of locksolution outside the catheter increases. Lock solution 190 can pass fromthe female luer to the meniscus 192 and to the sealing cover 120 througha gap 196. The gap 196 can be a passage between the central protrusion131 (a male luer) and the female luer 175. FIG. 12B shows an end crosssection view of the sealing cover of FIG. 12A. The gap 196 can be ringshaped and can permit the passage of lock solution 190 between thefemale luer 175 and the central protrusion 131.

Referring to FIG. 13, a side cross section view of a sealing cover 120made in accordance with an implementation of the invention, the sealingcover 120 almost completely inserted into a catheter hub. As the centralprotrusion 131 is inserted into the catheter hub, lock solution 190 isdisplaced from the female luer 175, such as through gap 196. Themeniscus 192 can progress further along the sealing cover threads 141 asthe lock solution 290 exits the catheter. A volume of lock solution 290is located between the sealing cover threads 141 and the catheter with asurface defined by the meniscus 192.

Further, in reference to FIG. 14, a side cross section view of a sealingcover 120 made in accordance with an implementation of the invention,the sealing cover 120 is fully inserted into a catheter. The centralprotrusion 131 can contact the female luer 175, such as to cause theflow of the lock solution 190 to cease. A volume of lock solution 190can thus be located between the catheter and the sealing cover 120.

In reference now to FIG. 15, a side cross sectional view of a sealingcover 120 made in accordance with an implementation of the invention,showing relative dimensions and volumes of the sealing cover 120components within the hub lumen 179 is shown. When the hub lumen 179 isfilled with a fluid, such as lock solution 190, to the end face 176, thedisplaced volume of fluid is equal to the volume of the centralprotrusion 131 in addition to the volume of the elongate member 133.Four cross-sectional planes are shown in FIG. 15: A-A′; B-B′; C-C′, andD-D′. Each of these pairs of planes define volumes within the interiorof the catheter. Thus, there is a volume within the catheter hub betweenplanes A-A′ and B-B′. This volume is occupied, in FIG. 15, by thecentral protrusion 131. A next volume is from B-B′ to C-C′. This volumeextends from the end of the central protrusion 131 to the end of pointwhere the elongate member 133 enters a constriction in the lumen in thehub. A third volume is located between C-C′ and D-D′, this volume in thedepicted embodiment has a particularly small cross sectional area,because it includes a relatively narrow portion of the lumen along withthe elongate member 133 extending into the lumen, such that the volumeis only the space between the elongate member and the walls of the lumenof the hub. A fourth volume, only partially shown in FIG. 15, is thevolume form D-D′ to the clamp positioned nearer the patient (not shown).

Upon insertion of the sealing cover into the proximal end of atransdermal catheter, the antimicrobial composition elutes into the locksolution 190. However, the configuration of the volumes, as shown inFIG. 15, is such that a large amount of the antimicrobial composition isinitially contained within the volume between B-B′ and C-C′. Some ofthis antimicrobial composition will eventually diffuse from the volumebetween B-B′ and C-C′ through the narrows between C-C′ and D-D′ toeventually arrive at the larger volume distal to D-D′. However, thegeometry is such that the concentration in the volume B-B′ to C-C′ has arelatively high level for an extended period of time (in typicalembodiments). This high concentration often results in precipitation ofsome of the antimicrobial composition onto the walls of the hub lumenbetween B-B′ to C-C′; as well as between C-C′ to D-D′. This precipitatedantimicrobial composition can prolong antimicrobial activity, and caneven provide protection between changes of the sealing cover 120,without exposing the patient's blood supply to high concentrations ofantimicrobial compositions.

Thus in certain embodiments, upon insertion of the elongate member andtapered member of the antimicrobial delivery device into the hub, theinterior of the catheter defines a first volume of lock solution (suchas B-B′ to C-C′), a second volume of lock solution (such as C-C′ toD-D′), and a third volume of lock solution (such as D-D′ to the catheterclamp), the first volume of lock solution having an average diametergreater than the average diameter of the second volume, the secondvolume of lock solution having an average cross sectional area less thanthe average cross sectional area of first volume and third volume, andthe third volume of lock solution having a cross sectional areasubstantially equal to the average lumen cross sectional area of thecatheter proximal to the clamp. In certain implementations the firstvolume of lock solution comprises lock solution located in the portionof the interior channel of the hub between the end of the tapered memberand the end of the tapered interior surface of the interior channel;wherein the second volume of is lock solution located between the end ofthe tapered interior surface of the interior lumen and the end of theelongate member; and wherein the third volume of lock solution compriseslock solution located within the catheter between the end of theelongate member and the clamp. Optionally the second volume is less thanthe first volume, and the first volume is less than the third volume. Incertain embodiments, upon insertion of the elongate member and taperedmember into the hub, antimicrobial concentration in the first volume isinitially higher than antimicrobial concentrations in the third volume.In certain embodiments, the antimicrobial concentration in the firstvolume after 48 hours is at least ten times higher than theantimicrobial concentration in the third volume. In certain embodiments,the amount of antimicrobial in the first and second volumes after 48hours is at least three times higher than the amount of antimicrobial inthe third volume.

In one embodiment a syringe can be used to fill the hub lumen 179, ifthe syringe is removed without injecting additional fluid as the syringeis removed, the hub volume will be under filled by the protrusion of thesyringe. In that case the displaced volume is equal to the volume of thecentral protrusion 131 in addition to the volume of the elongate member133, and minus the volume of the protrusion of the syringe. In anembodiment the volume of the protrusion of the syringe is 0.070 mL. Inan embodiment the volume of the central protrusion is 0.074 mL. In anembodiment the volume of the elongate member is 0.053 mL. In anembodiment the volume of the thread region of the sealing cover 120 is0.034 mL. It is desirable to wet the threads of the retaining ring andthe hub with the displaced lock solution; to ensure wetting of thethreads in this embodiment, the elongate member has a volume equal to orgreater than 0.030 mL.

FIG. 16A is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing a gap 197between the end face 176 of the hub of the catheter and the cover 120.FIG. 16B is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, also with a gap 197at the end face 176 of the catheter and the sealing cover 120.

In reference now to FIG. 17, an enlarged side cross sectional view of asealing cover 120 is shown; the sealing cover 120 is made in accordancewith an implementation of the invention, showing fluid on the threads ofthe proximal end of the catheter. As the sealing cover 120 was insertedinto the catheter 170, a meniscus 192 of lock solution 191 can form.Lock solution 191 containing an antimicrobial composition can be locatedbetween the sealing cover threads 141 and the catheter threads 178.

Referring to FIG. 18, a side cross sectional view of a sealing covermade in accordance with an implementation of the invention, showing atleast a portion of the fluid of FIG. 17 having evaporated leaving anantimicrobial residue is shown. With the passing of time, the locksolution 191 can evaporate leaving antimicrobial residue 291 on andbetween the sealing cover threads 141 and the catheter threads 178. FIG.19 is a side cross sectional view of a sealing cover made in accordancewith an implementation of the invention, showing rehydration of aportion of the antimicrobial residue of FIG. 18. As shown in FIG. 19,FIG. 20 is a side cross sectional view of a sealing cover made inaccordance with an implementation of the invention, showing at least aportion of the fluid of FIG. 19 having evaporated leaving anantimicrobial residue. As shown in FIG. 20, antimicrobial residue 291 isretained both on the threads of the sealing cover and on the catheterthreads.

In reference to FIG. 21, a sealing cover 120 is shown fully insertedinto a catheter 170. This embodiment contains an end seal 147. The endseal 147 provides additional benefit by preventing organisms fromentering the distal opening 144 thereby preventing the organisms fromsubsequently progressing through the void 194 where they could thencontaminate the end face 176 and female luer 175. Reducing the number oforganisms that can enter distal opening 144 can further reduce theincidence of CRBSI. The end seal 147 can be made of an elastic materialso it is sealing coverable of stretching over the catheter threads 178while the sealing cover 120 is being inserted, and it should alsoconform to the shape of the hub 172 so it creates an effectiveorganism-blocking seal. The end seal 147 is preferably made of a durablematerial so it does not rip or tear. It should generally be thin andflexible enough so it is easy to insert. The end seal 147 allows fluidto escape as the sealing cover 120 is being inserted onto the catheter170, yet acts as a barrier to substantially retain the lock solutionthat was pushed into the void 194 during insertion. In the preferredembodiment, this is accomplished by keeping the wall thin and flexibleenough to allow the increased pressure to escape where the end seal 147contacts the hub 172. In an example embodiment, the end seal 147 is overmolded onto the retaining ring 140. A thermoplastic elastomer, such asExxon Mobile's Santoprene, can be used. However, other materials, suchas silicone, may be suitable. In an embodiment, the end seal 147 is inthe range of 0.005 inch to 0.100 inch thick. In another embodiment, theend seal 147 is in the range of 0.010 inches to 0.040 inches thick.

The lock solution in void 194 also acts as a barrier to organisminfiltration. It contains antimicrobial composition that has dissolvedfrom the sealing cover 120 surfaces (elongate member 133, centralprotrusion 131, and catheter threads 178). In a desired embodiment, theantimicrobial levels result in an antimicrobial concentration that ishighly effectively at killing a broad spectrum of organisms.

In reference to FIG. 22, the sealing cover 120 is shown fully in crosssection inserted into a catheter 170. This embodiment can contain athread seal 148 that is impregnated with an antimicrobial composition inthe same amount as (and in place of) the amount on the sealing coverthreads 141 of FIG. 5C. The thread seal 148 provides additional benefitby preventing organisms from entering the distal opening 144 and, sincethe void 194 is now occupied with the thread seal 148, it preventsorganisms from progressing through the occupied void 194 where theywould otherwise contaminate the end face 176 and female luer 175.Reducing the number of organism that can enter distal opening 144 canfurther reduce the incidence of CRBSI.

The thread seal 148 is preferably made of an elastic foam material thatis sealing coverable of conforming around the catheter threads 178 whilethe sealing cover 120 is being inserted, and it should also conform tothe shape of the hub 172 so it creates an effective organism-blockingseal. The most distal end of the thread seal 148 often has a thin layerof closed polyurethane to help reduce evaporation of the solution. Thethread seal 148 is desirably made of a durable material so it does notrip or tear. One aspect of the thread seal 148 is that it allows fluidto cover the thread seal 148 as the sealing cover 120 is being insertedinto the catheter 170, yet it acts as a barrier to substantially retainthe lock solution that was pushed into the filled void 194 duringinsertion. In the preferred embodiment, this is accomplished bymanufacturing the thread seal 148 out of an open cell hydrophilicmedical polyurethane foam and having a thin layer of solid polyurethaneat the most distal end of the thread seal 148. The thread seal 148 andthe antimicrobial composition incorporated therein also acts as abarrier to organism infiltration. It contains antimicrobial compositionthat has dissolved from the sealing cover 120 surfaces (such as one ormore of the elongate member 133, central protrusion 131, and thread seal148).

FIG. 23A refers to an alternative embodiment of the sealing cover 120which possesses a tip 234 that has a diameter that is smaller than thediameter of the hub lumen 179 when the tip 234 is inserted into acatheter 170, but subsequently expands in size. This embodiment isespecially beneficial when the sealing cover 120 is used in a catheter170 that does not have a clamp for confining the solution, or in caseswhere it is desirable to further limit the amount of antimicrobialcomposition required (less is required because the volume of confinedsolution is lower). The tip 234 is shown in FIG. 23A in its unswollenstate during insertion in order to allow the elongate member to beeasily inserted and to minimize its potential for pushing organismsdistal to the tip 234 by a plowing action. The elongate member in apreferred embodiment remains sufficiently stiff while it is beinginserted onto into the catheter 170 and it does not require any extraparts or aids for insertion.

FIG. 23B refers to an alternative embodiment of the sealing cover 120 asdescribed in reference to FIG. 23A, except the tip 334 is shown in itsswollen state. In the depicted embodiment the diameter of the tip 334 isequal to the diameter of the hub lumen 179 in its swollen state; the tip334 preferably conforms to the surface of the hub lumen 179 as itswells. The swollen tip 334 is beneficial for confining the solution, orin cases where it is desirable to further limit the amount ofantimicrobial composition required (less is required because the volumeof confined solution is lower). The tip 334 is removable from the hublumen 179 when reasonable removal force is applied to the sealing cover120. This is achieved by choosing the material and size the tip 334 suchthat, when it is in its swollen state, the normal force that the tip 334applies to the wall of the hub lumen 179 is sufficiently low to allowacceptable removal force. In an example embodiment the diameter of theunswollen tip 234 (reference FIG. 23A) is 0.060 inches, the diameter ofthe confined swollen tip 334 is 0.098 inches (the same diameter as thehub lumen 179), and the diameter of the unconfined swollen tip is 0.110inches when placed in normal saline. However, these diameters will varyto match the diameter of the device that the sealing cover is being usedwith. The preferred unconfined swollen diameter (defined as the diameterthe tip will expand to if it is not confined by a lumen wall) isslightly larger than the diameter of the hub lumen 179. An additionalbeneficial effect of the swollen tip is that it produces a scrubbingeffect on the catheter wall that will physically remove organismsadhered to the interior wall section upon removing the sealing coverfrom the catheter.

In one embodiment, the tip is manufactured to produce anisotropicswelling, such that the diameter increases but the length does notsubstantially increase. In another embodiment the entire elongate memberis made of an anisotropically swelling material such that the diameterincreases but the length does not substantially increase.

In one implementation, the material of the tip 334 consists of aswellable polyurethane, such as Lubrizol TG-500, that has been heatfused onto the elongate member 133 which is a non-swellablepolyurethane, such as Lubrizol 1065D. These materials provide acceptableswelling, durability, strength and flexibility. The elongate member iscoated with antimicrobial composition in an amount sufficient to obtainan adequate antimicrobial effect, yet low enough to remain safe for thepatient.

In reference to FIG. 24 this alternative embodiment of the invention isuseful in applications where an elongate member will not fit into acatheter because the internal diameter of the catheter is too small,such as with peripherally inserted central catheters (PICC). In thisembodiment, the sealing cover 120 does not contain an elongate member asin previous embodiments. Instead, the sealing cover has a luer end face138 that is flat or slightly recessed, and the end face 138 is coatedwith an antimicrobial layer 139. The preferred type and amount ofantimicrobial in the antimicrobial layer 139 is the same as the elongatemember (reference the description for FIG. 5C). Similarly, the centralprotrusion 131 and the catheter threads 178 preferably contain the sametype and amount of antimicrobial composition as the other embodiments.The antimicrobial composition is preferably applied to the end faceusing a precision metering pump with 15% chlorhexidine acetate in amethanol solution. Other solvent, percentages and coating methods may beused.

In reference to FIG. 25A, an alternative embodiment of the invention isshown in which the sealing cover 420 is manufactured from twocomponents, a retaining ring 440 and an insert 130. It is desirable tohave a highly controlled and repeatable amount of antimicrobialcomposition placed upon the desired regions of the sealing cover 420. Itis also preferred to have different amounts of antimicrobial on thedifferent regions. It becomes easier to coat each region of the sealingcover 420 if the retaining ring 440 is not blocking access to thecentral protrusion 131 (and vice versa). This is accomplished bymanufacturing the sealing cover 420 as two separate pieces, theretaining ring 440 and the insert 130. The preferred amount ofantimicrobial composition within each region remains the same aspresented above (refer to Ref. 5C).

In reference to FIG. 25B, the insert 130 is coated with chlorhexidineacetate the elongate member 133 and along the central protrusion 131.The plate 132, sealing cover shoulder 136, and the retaining flange 137do not require coating. The two parts that are coated are the centralprotrusion 131 and the elongate member 133; contain the same amount ofantimicrobial as referenced above

In reference to FIG. 25C, the plate 132 at the proximal end of theinsert 130 has a hole 135. The purpose of this hole 135 is to improvemanufacturing. For instance, the hole 135 creates a convenient featurethat can be used for holding and rotating the insert 130 to allow thepart to be spun as it is being coated. The hole 135 also reducesshrinkage in the injected molded insert 130 by creating more uniformwall thickness.

In reference to FIG. 25D, the retaining ring 440 is a commerciallyavailable product from Value Plastics, Inc. with the exception that thesealing cover threads 141 are coated with an antimicrobial composition.The antimicrobial composition in the preferred embodiment ischlorhexidine acetate in the same preferred amount as disclosed above.The retaining ring 440 is readily coated using a spraying techniquewhere the retaining ring 440 is spun along its axis, and theantimicrobial is sprayed directly onto the sealing cover threads. As analternative coating method, the sealing cover threads 141 were coated byfilling the internal portion of the ring 440 with 7% chlorhexidinemethanol solution, subsequently draining the solution and allowing theparts to dry. This resulted in approximately 1.2 mg of chlorhexidineacetate on the sealing cover threads 141. The dose of antimicrobial maybe adjusted by adjusting the solution concentration.

In reference to FIG. 25E, the retaining shoulder 146 comes into contactwith the insert (not shown) when the insert is inserted inside theretaining ring 440. The proximal opening 143 is used to initiallyreceive the insert 130 (refer to FIG. 10F) during assembly. Theretaining fingers 145 are designed to retain the retaining ring 440 ontothe insert, as will be described in the reference below. The ringshoulder 146 helps secure the insert.

In reference to FIG. 25F, the preferred embodiment for the two-piecesealing cover 420 is shown. The insert 130 is shown fully inserted intothe retaining ring 440. The tip 134 was pushed through the proximalopening until retaining ring 440 bottomed out on the plate 132. Theretaining fingers 145 are engaged with the retaining flange 137 tosecure the retaining ring 440 on the insert 130.

It is desirable to have the retaining ring 440 not rotate freely on theinsert 130. Instead, it is preferred to have the torque be greater than0 pound-inches (lb-in) but less than 2.0 lb-in. In a more preferredembodiment, the torque is between 0.1 lb-in and 1.25 lb-in. In the mostpreferred embodiment, the torque is between 0.2 lb-in and 0.5 lb-in. Bycontrolling the diameter of the insert shoulder 136 such that itinterferes with ring shoulder 146, the torque can be controlled as shownin the graph depicted in FIG. 26.

It is preferred to keep the interference between the ring shoulder 146and the insert shoulder 136 within the range of 0.002 inch and 0.009inch in order to keep the rotation torque within an acceptable range.

Antimicrobial Composition

An antimicrobial composition can be incorporated both into the elongatemember material and/or on the elongate member surface of the presentinvention. In a preferred embodiment, the antimicrobial composition ischlorhexidine acetate; approximately 250 μg of chlorhexidine acetate iscoated onto a 17 mm long×1.9 mm diameter rod-shaped elongate member,resulting in a chlorhexidine acetate layer approximately 2 μm thickalong. The luer portion is coated with 50 μg of chlorhexidine acetate,resulting in a layer that is approximately 0.4 μm thick. It is alsopossible to inject an antimicrobial composition into the catheter usinga syringe, or to deliver antimicrobial compositions by way of theconnector tip cavity (dry dissolvable amount, applicable for Citrate orothers requiring large amounts of antimicrobial composition).

The elongate member has the added benefit of displacing fluid fromwithin the catheter as it is inserted, transferring the solution to theouter proximal region of the catheter connector (end face and threads).Antimicrobial composition from the sealing cover dissolves into thedisplaced fluid, and thereby disinfecting the proximal end of theconnector. Furthermore, when the fluid dries, it deposits a coating ofchlorhexidine acetate or other appropriate antimicrobial on theconnector as described above. As an alternative to using the elongatemember, is the chlorhexidine acetate or other antimicrobial compositionmay be delivered by a coating on a luer tip (such as 250 μg ofchlorhexidine acetate in a layer that is approximately 20 μm thick).

An antimicrobial composition is located on the outer surface of theelongate member, the male luer connector, and the retaining ring. Theantimicrobial composition elutes from the elongate member afterinsertion of the elongate member/rod into a catheter. When the system isinserted into the catheter, the antimicrobial composition dissolves intothe fluid contained within the catheter, thus coming into contact withinfectious organisms that might be present along the connector surfacesand lumen wall of the catheter or in solution. Additionally, theantimicrobial composition and any infectious organisms are confinedtogether in the small space along within the catheter. Another benefitis that the confining action of the clamp traps any infectious microbeswithin the catheter and prevents them from being transmitted to otherareas of the catheter or to the body to prevent a systemic infection.

The antimicrobial compositions should kill and/or provide stasis ofGram-positive and Gram-negative bacteria and fungi. The agents may alsohave efficacy at killing organisms within an established biofilm and/ordegrading the extracellular matrix of the film. However, this is notnecessary for the invention to be beneficial because the invention isdesigned to kill organisms before they have an opportunity to form abiofilm. The preferred antimicrobial composition is chlorhexidineacetate, also known as chlorhexidine diacetate. Other compoundscontaining chlorhexidine may be used (such as chlorhexidine free base,chlorhexidine gluconate and chlorhexidine with dyes). Chlorhexidineacetate has an advantage over chlorhexidine gluconate because the risksassociated with para chloroaniline may be minimized. Other suitableantimicrobial compositions may also be used. In general, the preferredantimicrobials are soluble in water, they have a history of clinical usewith a demonstrated safety profile, they are antibiotic-free, they canbe applied onto a medical device, and they can be subsequently dissolvedinto a composition having an effective concentration to inhibit growthof bacterial and fungal organisms. Suitable materials includechlorhexidine, chlorhexidine salts (such as chlorhexidine acetate orchlorhexidine gluconate), tetrasodium ethylenediaminetetraacetic acid(tetrasodium EDTA), sodium citrate (yielding a concentration of 30% orhigher), iodine, taurolidine, disodium EDTA, silver compounds (includingsilver nanoparticles and ions), silver sulfadiazine, and, triclosan.

While one particular drug or antimicrobial composition may providerelief from a wide range of challenging organisms that could potentiallylead to catheter-related bloodstream infection, two or more agents maybe used to increase efficacy against a broad range of infectiousorganisms (bacteria and fungi).

In particular, catheter-related infections arise from three broadclasses of organisms: fungi, Gram-negative bacteria, and Gram-positivebacteria. If an antimicrobial composition can be identified that wouldabate one or two of these types of organisms, while this would certainlybe beneficial, it would leave the patient vulnerable to the remainingtype(s). By pairing agents with different modes of action, infections byan increased spectrum of organisms can be prevented. This synergy wouldlikely lead to further decreases in catheter-related morbidity andmortality, lessening the impact of the implanted catheter on thepatient's quality of life. The preferred combinations of antimicrobialcompositions are chlorhexidine acetate and EDTA, silver sulfadiazine andsodium dodecyl sulfate, and silver sulfadiazine and methylene blue.

Although treating, preventing, and eliminating infectious organisms forthe prevention of infections is the primary use of the sealing cover,ancillary benefits can also be envisioned which would involveincorporating additional agents. An antithrombotic agent eluting fromthe elongate member can be used to improve the action of the heparinused currently in the lock solution. An enzyme or agent which promoteddegradation of the extra-cellular matrix of biofilm (generally composedof polysaccharides) could enable use of the sealing cover for treatmentas well as prevention.

In principle, antibiotics (rifampin, minocycline, etc.) can beincorporated into the sealing cover or similar device and be aseffective as non-antibiotic antimicrobials. However, continuous exposureto one antibiotic can lead to antibiotic resistant bacteria strains, forexample, methicillin resistant S. aureus (MRSA). Therefore, thepreferred embodiment uses an antimicrobial composition selected from thesubset of those which are not antibiotics. If, for some reason, anantibiotic is used, the risk of developing antibiotic resistant strainsof bacteria may be mitigated by preparing a second, complimentary,sealing cover containing a different antibiotic. By using the twosealing covers in an alternating fashion with successive dialysistreatments, infectious organisms that are resistant to one antibioticmay be killed by the other.

When the elongate member is inserted into the hub, it creates aconstriction within the interior channel of the hub which helps reducediffusion of the antimicrobial composition and organisms from the hub tothe more distal portions of the catheter. Since a large percentage oforganisms are believed to enter the catheter at the hub, it is importantto kill organisms in this region before they have an opportunity tospread throughout the catheter. The restriction created by the elongatemember within the hub is effective at creating a confinement within thehub region. For example, the invention was manufactured using injectionmolding such that the tapered luer member and the elongate member wererigidly affixed to one another as a single piece of polymer. Thediameter of the elongate member was 0.078 inch, and the diameter at thenarrowest section of the hub channel was 0.100 inch. In this embodiment,inserting the elongate member into the hub reduced the cross-sectionalarea of the channel by over 60%, and creates a substantially greaterreduction in diffusion.

After injection molding, the tapered member and the elongate member weresubsequently coated with 60 μg and 225 μg of chlorhexidine acetate,respectively. The length of the elongate member was 0.700 inches. Withthe device fully inserted into a catheter, the elongate member extendedalong the hub's interior channel, and the elongate member ended near theend of the hub. Since the elongate member remained substantially withinthe hub, the elongate member was readily inserted into the catheter evenwhen the catheter clamp was placed in its most proximal position.

A series of tests were performed using the above described embodiment.In one experiment, catheters were filled with lock solution and thedevices were inserted. The catheters and devices were left for 48 hours.After the 48 hours, the devices were removed from the catheters and theamount of chlorhexidine within the hub region and within the remainderof the catheter region as measured for each of the catheters. Theresults demonstrated that the invention is highly effective atmaintaining the chlorhexidine within the hub region. On average, over80% of the chlorhexidine remained in the hub region after 48 hours; 20%was in the distal region of the catheter. The experiment was repeated atvarious antimicrobial doses and within heparin and saline locksolutions. A total of 50 devices were tested and similar results wereobtained. In another experiment, the above described embodiment wasplaced into catheters that had been filled with a lock solutioncontaining approximately 200,000 colony forming units per catheter of adifficult to kill microorganism, Pseudomonas aeruginosa. After 48 hoursthe devices were removed from the catheters. The catheters were thentested for the presence of the microorganism. All microorganisms werekilled in all of the catheters, further demonstrating the effectivenessof the invention.

Experiments have been conducted to examine the performance of an exampleembodiment of the invention, which is called “Pursuit Vascular'sClearGuard HD” or the “ClearGuard HD”. These experiments demonstratethat the ClearGuard HD is effective at substantially reducing organismswithin catheters as intended. Two of the experiments are highlightedbelow.

In an experiment conducted at Pursuit Vascular, coated sealing coverswere effective at consistently transferring more than 50 μg ofchlorhexidine acetate (also referred to as chlorhexidine diacetate) ontothe catheter's threads with a single connection. Such transfer providesthe catheter with a means of further reducing infection-causingorganisms which is replenished with every use of the invention. 10 μg ormore of chlorhexidine is effective at reducing bacteria and otherinfection-causing organisms at the threads, and further preventing theorganisms from infiltrating the catheter's connector end face, luer andlumen. Chlorhexidine acetate has a wide safety profile when used outsidethe catheter where there is little risk of it entering the bloodstream.A preferred range of chlorhexidine on the sealing cover threads is 100μg to 2500 μg. 500 μg to 1200 μg is more preferred.

For instance, if using a chlorhexidine based antimicrobial,approximately 50 μg of chlorhexidine acetate can be effective in someembodiments. This was demonstrated in an experiment conducted at PursuitVascular in which 50 μg of chlorhexidine was coated on the sealingcover's luer portion. The sealing covers containing the coated luerskilled all of the Candida albicans that were seeded within thecatheter's luer region. Within the same experiment, the Candida albicansremained viable when uncoated sealing covers were used. Greater than 5μg chlorhexidine acetate on the luer region is effective; 10 μg to 300μg is preferred, and 30 μg to 80 μg is most preferred.

Laboratory testing conducted for Pursuit Vascular, Inc. demonstratedthat 250 μg of chlorhexidine acetate on the elongate member producesgreater than a 10,000× reduction in number of infection-causingorganisms when the sealing cover is used in a standard hemodialysiscatheters containing saline, heparin-saline, or saline with 4% sodiumcitrate. The safety profile of the invention can be enhanced by limitingthe amount of chlorhexidine acetate available to enter the bloodstream,the preferred maximum amount of chlorhexidine acetate on the elongatemember is 2000 μg, more preferred is 1000 μg, and most preferred is 350μg.

Experiment 1

The objective of this experiment was to assess the antimicrobialeffectiveness of Pursuit Vascular's ClearGuard HD device in the mostdifficult clinically-relevant model. Since the ClearGuard HD is intendedto be placed in catheter hubs, but not extend into the extension tubing,the catheter model was chosen to be a female luer connector, extensiontube and clamp. The total length of the female luer connector and theextension tubing was manufactured to maximize the length and volume thatwould be expected to be encountered clinically. Candida albicans(fungus) was chosen as the challenge microorganism, because in previoustests Candida albicans was shown to be the most challengingmicroorganism for the ClearGuard HD to eradicate. Candida albicans wereadded to three different lock solutions: heparin-serum, saline-serum,and SDB broth. These solutions represent the most relevant (andchallenging) solutions that would be expected clinically. The catheterswere filled with the lock solutions and Candida albicans, next thesealing covers (either the ClearGuard HD or a standard sealing cover)were secured, and then the catheters were incubated for approximately 46hours to simulate the time between dialysis sessions. After incubation,the sealing covers were removed and the lock solution was tested for thepresence of organisms.

Experiment 1 results: The organism count is shown in FIG. 27 forClearGuard HD sealing covers and standard sealing covers (shown as “withCGHD” and “without CGHD”, respectively).

Organism Count at Study End With Without Organism Solution CGHD CGHDReduction* 5000 IU/ml Hep-Saline 0.0E+00 3.6E+06 3.6E+06 with 25% SerumSaline with 25% Serum 0.0E+00 3.8E+03 3.8E+03 SDB Broth 0.0E+00 7.7E+087.7E+08 *Actual reduction in organism count is likely higher thancalculated in this test because no organisms survived in the CGHD arm ofthe study.

The antimicrobial effectiveness of the ClearGuard HD was assessedagainst Candida albicans, the microorganism which has been the mostdifficult to eradicate when tested in a clinically relevant cathetermodel containing the most challenging and clinically relevant fluids.

All test samples using the ClearGuard HD had complete kill of theCandida albicans. In comparison, all control samples demonstrated growthof the CA. Since no Candida albicans survived during the ClearGuard HDportion of the test, the actual Candida albicans reduction may besignificantly higher (better) than the sensitivity of this test. Theminimum reduction of Candida albicans, when using the ClearGuard HD inplace of a standard sealing cover, was shown to be:

-   -   a. 3.6×10⁶ CFU/ml for Heparin with 25% Serum    -   b. 3.8×10³ CFU/ml for Saline with 25% Serum    -   c. 7.7×10⁸ CFU/ml for SDB Broth        This test demonstrates that the ClearGuard HD produces a        significant reduction in Candida albicans within a clinically        relevant catheter and with clinically solutions. Candida        albicans was previously shown to be the most difficult organism        to reduce of the other clinically relevant microorganisms        tested, therefore concluding that the ClearGuard HD produces        broad-spectrum reduction in clinically relevant microorganisms.

Experiment 2

The objective of this experiment was to assess the relative rate ofmicroorganism contamination in hemodialysis catheter lumens when usingthe ClearGuard HD versus standard sealing covers in a simulated clinicalenvironment. This experiment was intended to examine the effectivenessof the ClearGuard HD at preventing microorganism contamination ofhemodialysis catheter lumens (both proximal and distal to the extensiontubing clamp), compared to standard sealing covers in a simulatedclinical environment. Growth media was used inside of the catheterinstead of the standard lock solution in order to provide an extremelysensitive means of detecting whether any microorganisms entered insidethe catheter.

During clinical use, hemodialysis catheter hubs are routinely exposed tomicroorganisms because the catheter and hub lies against the patient'sskin. All commercially available catheter sealing covers are primarilydesigned to keep fluid inside the catheter lumen but they are not welldesigned for preventing microorganisms from reaching and colonizingcatheter lumens.

In order to compare whether the rate of microorganism colonization isaffected by sealing cover type (ClearGuard HD versus standard sealingcover), twenty identical catheters were affixed to clothing, in a mannerthat would keep the catheters in contact with human skin, which occursduring clinical use. The catheters were kept in contact with the skinfor a maximum of 26 days. Once a catheter's lumen was determined to becontaminated, the catheter was allowed to be removed from the study. Thetest consisted of two arms: 1) the ClearGuard HD arm, and 2) thestandard sealing cover arm. Except for the sealing cover type used, thetwo arms were identical in all other ways (i.e., identical catheters,solutions, handling, etc.).

The study was designed to mimic the hemodialysis clinical practice asclosely as practical. The entire volume of lock solution, including thesolution distal to the clamp, was included in the microbiologicaltesting to ensure with high probability that if any microorganisms werepresent anywhere within the catheter that they would be detected.Standard microbiological techniques were used to test for the presenceof organisms.

The number of catheters that remained free from microorganismcontamination as time progressed is illustrated in FIG. 28. Withinfourteen days, all catheters using standard sealing covers had becomecontaminated, while none of the catheters using the ClearGuard HD hadbecome contaminated throughout the full twenty-six days of theexperiment.

This experiment showed that, when catheters were filled with a growthmedia, were worn to simulate actual patient end use and were subjectedto a standard dialysis fluid exchange schedule, the catheters usingstandard sealing covers became contaminated with microorganisms at amean time to failure of 8.9 days, and all of these catheters (10 out of10) became contaminated by 14 days. In comparison, none of the cathetersusing the ClearGuard HD (0 out of 10) became contaminated throughout theentire 26 day test. The ClearGuard HD performs significantly better thanstandard sealing covers (the current standard of care) at reducingmicroorganism contamination inside of catheters in a simulated clinicalenvironment.

Experiment 3

The objective of this experiment was to confirm whether an adequateamount of antimicrobial composition elutes from the sealing cover into acatheter within an acceptable timeframe. Catheters were each filled withone of three lock solutions: sodium heparin, sodium citrate, and sodiumchloride (saline). Sealing covers were then placed on the catheter hubsfor the following durations: less than 10 seconds, 6 hours, 12 hours, 24hours, 48 hours, and 72 hours. Five replicates were tested at each timepoint and each lock solution. At the end of the time period, theClearGuard HDs were removed from the catheters, and the chlorhexidinethat eluted into each of the catheter was measured.

Within 6 hours of the ClearGuard HD sealing cover being inserted intothe catheter, the average elution was over 20 μg in all lock solutions(equating to more than 10% of the antimicrobial present on the elongatemember). The amount of antimicrobial composition eluted increased withtime, averaging greater than 30 μg (greater than 15% of theantimicrobial present on the elongate member) in all lock solutions at72 hours.

This test confirmed that the sealing cover is capable of delivering anadequate amount of antimicrobial agent into a catheter within 6 hours ofbeing inserted.

Experiment 4

The objective of this experiment was to confirm whether a sealing coveris capable of delivering more antimicrobial composition into the hub ofa catheter than it delivers into the other regions of the catheter.Experiments were performed to quantify the distribution of thechlorhexidine along the length of the catheter resulting from aClearGuard HD sealing cover being inserted into the catheter. Thefollowing test results demonstrated that the sealing cover is capable ofpreferentially delivering more antimicrobial agent into the hub of thecatheter in comparison to the remainder of the catheter, and that thispreferential distribution is substantial even after the sealing coverhas been in place for 48 hours.

In this experiment, a catheter was filled with heparin saline locksolution and the catheter was clamped 96 millimeters from the proximalend face of the hub. A sealing cover was then inserted into the catheterand allowed to sit for 48 hours, representing the time that the sealingcover would commonly remain in place in a clinical setting. After the 48hour time period elapsed, the catheter was isolated into regions usinghemostats in order to allow the amount of chlorhexidine to be measuredin each of the regions. The total amount of chlorhexidine present ineach region was measured using HPLC, and was performed using 10 testreplicates.

FIG. 29 shows the location of the isolated regions. Proximal to thecatheter clamp, there were four regions consisting of the hub region andthree extension tubing regions (called segment 1, 2 and 3). Each ofthese regions was 24 mm long. These regions combined form a proximalregion to the catheter. The final region was distal to the clamp,forming a distal region to the catheter. After the 48 hours, the sealingcovers were removed and measurements were performed. Ten test replicateswere tested and the average amount of antimicrobial in each region ispresented in FIG. 30.

As indicated in FIG. 30, on average approximately 28 μg of chlorhexidinehad eluted into the heparin-saline lock solution, with 20 μg (72% of theeluted amount) being contained in the hub region, which is more than allother regions combined. The hub contained 0.084 mL of lock solution;therefore, the hub contained over 235 μg/mL of chlorhexidine. Incomparison, segments 1, 2 and 3 each contained approximately 0.180 mL oflock solution, producing an average chlorhexidine concentration of 29,11, and 3 μg/mL in segments 1, 2, and 3, respectively. There wasinitially an average of 214 μg of chlorhexidine acetate on the elongatemember. Therefore approximately 13% of the antimicrobial that wasoriginally present on the elongate member had eluted into the locksolution.

This test was repeated using sodium citrate and saline lock solutions.In all cases, the average amount of chlorhexidine in the hub exceeded200 μg/mL, and the largest amount of antimicrobial was present in thehub, with less contained in the regions distal to the hub. In all cases,the amount of antimicrobial was substantially greater in the hub due toprecipitate adhering to the walls of the catheter and theconfining/flow-restricting effect of the elongate member within the hub.When heparin-saline is used as the lock solution, more than 50% of theantimicrobial composition that elutes into the lock solutionprecipitates onto the interior wall of the catheter.

It is desirable to have a high concentration of antimicrobialcomposition in the hub region, especially along the walls of the hub, inorder to kill the organisms before they have a change to migrate intothe distal regions of the catheter. Having no measurable antimicrobialcomposition distal to the clamp is also advantageous because itsubstantially reduces the potential for antimicrobial agent entering thepatient's bloodstream.

Experiment 5

The objective of this experiment was to demonstrate that certainimplementations of the sealing cover of the present invention arecapable of depositing an antimicrobial composition onto the internal andexternal surfaces of a catheter. One of the greatest drawbacks ofpresent day antimicrobial treated catheters is that the antimicrobialwears off quickly over time. In the case of commercially availableantimicrobial catheters, within two days of use over 50% of theantimicrobial may be washed away.

In this experiment, catheters which initially contained no antimicrobialcomposition were used with ClearGuard HD sealing covers in a manner thatwas intended to simulate hemodialysis use over multiple hemodialysissessions. Each of the catheters were filled (locked) with saline, wereclamped, and new sealing covers were inserted. Each sealing coverremained on the catheter for two to three days, which is standardpractice in dialysis. After the two to three day period, the sealingcovers were removed and the catheters were aspirated and flushed perclinical protocol. At this point the catheters were either tested toquantify the amount of antimicrobial on the surfaces (which removed themfrom further simulated dialysis), or they were subjected to another usethat included simulated dialysis (saline flowing the catheter at 350mL/hour), followed by insertion of a new sealing cover for two to threedays, until its removal and the catheter being aspirated and flushed.Successive rounds were continued until all of the desired time pointdata were gathered. Four lots of 3-5 catheters were used: one lot foreach time point of 1 use, 3 uses, 5 uses and 9 uses. A new sealing coverwas inserted for each catheter use, thus 90 sealing covers were used intotal.

The quantity of antimicrobial on the internal and external cathetersurfaces was measured at the specific time points, and the results ofthis experiment are shown in FIG. 31. A logarithmic fit to the data wasperformed, showing that the sealing covers apply antimicrobialcomposition to the catheters and that the amount of antimicrobialcomposition on both the internal and external catheter surfacesincreases with multiple uses, but approaches an upper limit withmultiple uses. On the internal surface, the majority of theantimicrobial is contained within the hub. On the external surface theantimicrobial is contained on the proximal hub end face and the threads.The residual protection on the catheter surfaces alone is sufficient toprovide substantial protection against infectious organisms. The sametest was performed using heparin-saline lock solution in place of thesaline lock solution; this test also demonstrated that the sealingcovers apply antimicrobial composition to the catheters.

Experiment 6

The objective of this experiment was to confirm that the sealing coverof certain embodiments of the invention are capable of killing a broadspectrum of microorganisms in a clinically relevant test model. A testwas designed to evaluate effectiveness at killing organisms in catheterhubs. The test was designed to simulate a scenario where thehemodialysis hub becomes challenged with microbes at the end of adialysis session, and a sealing cover is employed to reduce or eliminatethe contaminating organisms.

In addition to the test devices, control devices were used to allow fora comparison between the efficacy of the invention (test device)compared to an uncoated sealing cover (control device). Each catheterwas inoculated with organisms from one of the multiple organism strainsthat were tested. After the catheters were inoculated, a sealing coverwas inserted into each of the inoculated catheters. Three testreplicates were used for each of the organism strains, in both the testand control arms. After two days of incubation (representing the timebetween dialysis sessions), the sealing covers were removed andmicrobiologic testing was performed to quantify the number of organismsremaining within each catheter. The results showed that the sealingcover of this invention produced a 4-log (10,000 fold) or greaterreduction in the number of organisms in the catheter hub against each ofthe following organisms:

-   -   Staphylococcus aureus    -   Staphylococcus aureus (MRSA)    -   Staphylococcus epidermidis (MRSE)    -   Enterococcus faecium (FRE)    -   Pseudomonas aeruginosa    -   Acinetobacter baumannii    -   Escherichia coli    -   Candida albicans    -   Candida paratropicalis

The organisms in the above list account for approximately 70% of allcatheter-associated bloodstream infections, and they includegram-negative bacteria, gram-positive bacteria, and fungi. Therefore,the sealing cover of this invention is effective at killing a broadrange of clinically relevant organisms within a catheter.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope of theinvention.

1. A packaging container for securing antimicrobial caps prior to use,the packaging container comprising: a body having: a first end, thefirst end having a first substantially circular opening having a firstcentral axis perpendicular to the opening, the opening leading to afirst volume within the body, a second end, the second end having asecond substantially circular opening having a second central axisperpendicular to the opening leading to a second volume within the body,the first and second openings configured to each hold one antimicrobialcap; wherein the first opening and the second opening are locatedsubstantially opposite one another; wherein the first and second centralaxes are offset from one another.
 2. The packaging container of claim 1,wherein each of the first and second volumes have an elongateorientation with a length and a diameter, wherein the length is greaterthan the diameter.
 3. The packing container of claim 1, wherein thefirst and second volumes define axes along their longest dimension, andthese axes are offset from one another.
 4. The packaging container ofclaim 1, wherein each of the antimicrobial caps comprise an elongatemember, and the first and second volumes are each constructed to receiveone of the elongate members.
 5. The packaging container of claim 1,wherein the first and second central axes are substantially parallel. 6.The packaging container of claim 1, wherein the first and second volumesare intersected by a plane that is perpendicular to the first and secondcentral axes, and the first and second volumes are non-communicating toone another.
 7. The packaging container of claim 1, configured such thatthe antimicrobial caps are retained on the body oriented substantially180 degrees from one another.
 8. The packaging container of claim 1,wherein the body has substantially uniform wall thicknesses defining thefirst and second volumes.
 9. The packaging container of claim 1, whereinthe first and second volumes are separate from one another.
 10. Thepackaging container of claim 1, wherein the antimicrobial caps compriseelongate members, and wherein the packaging container is constructedsuch that the elongate members project into the first and second volumesand can be secured without the elongate members contacting interiorsurfaces of the first or second volumes.
 11. The packaging container ofclaim 1, wherein the body is constructed from a single plasticcomponent.
 12. A packaging container for securing antimicrobial capsprior to use, the packaging container comprising: a body having: a firstend, the first end having a first opening leading to a first volumewithin the body, a second end, the second end having a second openingleading to a second volume within the body, wherein the first and secondopenings are configured to each hold the antimicrobial caps; wherein thefirst volume has a first central axis through the first opening andthrough the first volume, and the second volume has a second centralaxis through the second opening and the second volume, and wherein thefirst and second central axes are substantially parallel.
 13. Thepackaging container of claim 12, wherein each of the first and secondvolumes have an elongate orientation with a length greater than adiameter.
 14. The packaging container of claim 12, wherein the first andsecond axes are offset from one another.
 15. The packing container ofclaim 12, wherein the first and second volumes are intersected by aplane that is perpendicular to the first and second central axes, andthe first and second volumes are non-communicating to one another. 16.The packaging container of claim 12, wherein the first and secondvolumes are each constructed to receive an elongate member on a capsecured to each of the openings on the body.
 17. The packaging containerof claim 12, wherein the first and second volumes do not overlap oneanother.
 18. A packaging container for securing antimicrobial caps priorto use, the packaging container comprising: a body having: a first end,the first end having a first opening leading to a first volume withinthe body, a second end, the second end having a second opening leadingto a second volume within the body, the first and second openingsconfigured to each hold the antimicrobial caps; wherein the first volumehas a first central axis through the first opening and through the firstvolume, and the second volume has a second central axis through thesecond opening and second volume; and wherein the first and secondvolumes do not overlap one another.
 19. The packaging container of claim18, wherein each of the first and second volumes have an elongateorientation with a length greater than their width. 20.-26. (canceled)